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EPOPROSTENOL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Epoprostenol is a prostacyclin direct vasodilator and inhibitor of platelet aggregation used to treat pulmonary arterial hypertension for improvement of exercise capacity.

Specific Substances

    1) Epoprostenol Sodium
    2) CAS 35121-78-9 (epoprostenol)
    3) CAS 61849-14-7 (epoprostenol sodium)
    1.2.1) MOLECULAR FORMULA
    1) C20H31NaO5 (Prod Info FLOLAN(R) intravenous injection, 2015)

Available Forms Sources

    A) FORMS
    1) Epoprostenol is available as 0.5 mg or 1.5 mg freeze-dried powder in a single use vial for IV administration following reconstitution (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) USES
    1) Epoprostenol is approved to treat pulmonary arterial hypertension (PAH; WHO Group I) for improvement of exercise capacity. In order to establish effectiveness, the majority of patients in clinical trials with New York Heart Association Functional Class III to IV symptoms had either idiopathic or heritable PAH or PAH associated with connective tissue diseases (Prod Info FLOLAN(R) intravenous injection, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Epoprostenol is approved to treat pulmonary arterial hypertension (PAH; WHO Group I) for improvement of exercise capacity.
    B) PHARMACOLOGY: Epoprostenol is a naturally occurring prostaglandin and a known metabolite of arachidonic acid. It directly stimulates vasodilation of pulmonary and systemic arterial vascular beds, and inhibits platelet aggregation.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects following therapeutic administration include jaw pain, nausea and vomiting, dizziness, headache, and musculoskeletal pain.
    2) LESS COMMON: Other adverse effects reported less frequently include flushing, hypotension, tachycardia, anorexia, diarrhea, dermal reactions (ulcers, eczema, rash, urticaria), anxiety, nervousness, hyperkinesias, tremor, hyperesthesia, hypesthesia, paresthesia, chills, fever, sepsis, and flu-like symptoms. An increased risk of bleeding due to inhibition of platelet aggregation can occur.
    3) SUDDEN DRUG WITHDRAWAL: Abrupt drug withdrawal or sudden large reduction in dosage may result in symptoms associated with rebound pulmonary hypertension (eg, dizziness, dyspnea, asthenia). A fatality occurred in one patient during a clinical trial due to interruption of epoprostenol therapy.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Clinical effects are anticipated to be an extension of the adverse effects seen with therapeutic use. Excessive doses may result in flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Fatal occurrences of hypoxemia, hypotension, and respiratory arrest have occurred following overdosage of epoprostenol sodium. One patient experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecified concentration). Symptoms resolved when the infusion was stopped.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Chills/fever/sepsis/flu-like symptoms were reported with epoprostenol therapy during clinical trials.
    0.2.20) REPRODUCTIVE
    A) Epoprostenol is classified as FDA pregnancy category B. Although adequate and well-controlled studies have not been conducted on the effect of epoprostenol in pregnant women, animal studies have indicated no evidence of fetal harm following maternal administration of epoprostenol doses up to 4.8 times the recommended human dose. It is unknown if epoprostenol is excreted in human milk.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, human carcinogenicity studies have not been conducted.

Laboratory Monitoring

    A) Monitor blood pressure frequently.
    B) Monitor for evidence of bleeding. Obtain a baseline CBC with differential in patients at risk for bleeding (eg, patients currently taking anticoagulants); repeat as indicated.
    C) Monitor ECG and institute continuous cardiac monitoring following a significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Because of the short half life of epoprostenol (6 minutes in vitro), toxic effects after overdose are expected to be relatively short lived. Monitor blood pressure frequently. Manage mild hypotension with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Monitor ECG and institute continuous cardiac monitoring following a significant overdose. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops. Severe thrombocytopenia and hemorrhage may develop due to epoprostenol's mechanism as a platelet aggregation inhibitor; monitor platelets closely and transfuse platelets and/or packed red cells in patients with severe thrombocytopenia, anemia or hemorrhage.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with pulmonary toxicity or severe hemodynamic instability.
    E) ANTIDOTE
    1) None
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication.
    2) Abrupt withdrawal of therapy or sudden large reductions in dose may result in symptoms associated with rebound pulmonary hypertension (eg, dizziness, dyspnea, asthenia).
    H) PHARMACOKINETICS
    1) Epoprostenol is extensively metabolized via hydrolysis and enzymatic degradation. The half-life is approximately 6 minutes.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers).
    2) Includes other agents that inhibit platelet aggregation (eg, anticoagulants, antiplatelet agents).

Range Of Toxicity

    A) TOXICITY: Acute toxic dose has not been established. One patient experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecific concentration). Following the discontinuation of epoprostenol, the patient regained consciousness within seconds.
    B) THERAPEUTIC DOSE: ADULTS: Initially, 2 ng/kg/min IV; may be titrated in 1 to 2 nanograms/kg/min increments at intervals of at least 15 minutes to allow for assessment of clinical response. PEDIATRIC: Safety and effectiveness have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Epoprostenol is approved to treat pulmonary arterial hypertension (PAH; WHO Group I) for improvement of exercise capacity.
    B) PHARMACOLOGY: Epoprostenol is a naturally occurring prostaglandin and a known metabolite of arachidonic acid. It directly stimulates vasodilation of pulmonary and systemic arterial vascular beds, and inhibits platelet aggregation.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects following therapeutic administration include jaw pain, nausea and vomiting, dizziness, headache, and musculoskeletal pain.
    2) LESS COMMON: Other adverse effects reported less frequently include flushing, hypotension, tachycardia, anorexia, diarrhea, dermal reactions (ulcers, eczema, rash, urticaria), anxiety, nervousness, hyperkinesias, tremor, hyperesthesia, hypesthesia, paresthesia, chills, fever, sepsis, and flu-like symptoms. An increased risk of bleeding due to inhibition of platelet aggregation can occur.
    3) SUDDEN DRUG WITHDRAWAL: Abrupt drug withdrawal or sudden large reduction in dosage may result in symptoms associated with rebound pulmonary hypertension (eg, dizziness, dyspnea, asthenia). A fatality occurred in one patient during a clinical trial due to interruption of epoprostenol therapy.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Clinical effects are anticipated to be an extension of the adverse effects seen with therapeutic use. Excessive doses may result in flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Fatal occurrences of hypoxemia, hypotension, and respiratory arrest have occurred following overdosage of epoprostenol sodium. One patient experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecified concentration). Symptoms resolved when the infusion was stopped.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Chills/fever/sepsis/flu-like symptoms were reported with epoprostenol therapy during clinical trials.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Chills/fever/sepsis/flu-like symptoms were reported in 25% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 11% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) Chills/fever/sepsis/flu-like symptoms were reported in 13% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 11% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) Hypotension was reported in 13% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 0% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) During clinical trials, excessive epoprostenol doses were associated with the development of hypotension. In clinical practice, epoprostenol overdose has resulted in hypoxemia, hypotension, and respiratory arrest resulting in death (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) One patient with pulmonary arterial hypertension associated with scleroderma spectrum of diseases experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecified concentration). Symptoms resolved when the infusion was stopped (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia was reported in 35% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 24% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia was associated with excessive doses of epoprostenol during clinical trials (Prod Info FLOLAN(R) intravenous injection, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY ARREST
    1) WITH POISONING/EXPOSURE
    a) In clinical practice, epoprostenol overdose has resulted in hypoxemia, hypotension, and respiratory arrest resulting in death (Prod Info FLOLAN(R) intravenous injection, 2015)
    B) PULMONARY EMBOLISM
    1) WITH THERAPEUTIC USE
    a) Pulmonary embolism was reported during postmarketing surveillance; however, causality is uncertain (Prod Info FLOLAN(R) intravenous injection, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported in 83% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 33% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Headache was reported in 46% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 5% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Headache was associated with excessive doses of epoprostenol during clinical trials (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 83% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 70% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    C) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Anxiety/nervousness/hyperkinesias/tremor were reported in 21% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 9% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Anxiety/nervousness/hyperkinesias/tremor were reported in 7% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 5% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    D) LOSS OF CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) One patient with pulmonary arterial hypertension associated with scleroderma spectrum of diseases experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecified concentration). Symptoms resolved when the infusion was stopped (Prod Info FLOLAN(R) intravenous injection, 2015).
    E) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesia/hyperesthesia/hypesthesia were reported in 12% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 2% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Paresthesia/hyperesthesia/hypesthesia were reported in 5% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 0% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    F) TREMOR
    1) WITH THERAPEUTIC USE
    a) Tremor/hyperkinesias/nervousness/anxiety were reported in 21% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 9% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Tremor/hyperkinesias/nervousness/anxiety were reported in 7% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 5% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were reported in 67% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 48% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Nausea and vomiting were reported in 41% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 16% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting were associated with excessive doses of epoprostenol during clinical trials (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) One patient with pulmonary arterial hypertension associated with scleroderma spectrum of diseases experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecified concentration). Symptoms resolved when the infusion was stopped (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 37% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 6% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Diarrhea was reported in 50% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 5% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea was associated with excessive doses of epoprostenol during clinical trials (Prod Info FLOLAN(R) intravenous injection, 2015).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia was reported in 66% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 47% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Hepatic failure was reported during postmarketing surveillance; however, causality is uncertain (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) SPLENOMEGALY
    1) WITH THERAPEUTIC USE
    a) Splenomegaly and hypersplenism were reported during postmarketing surveillance; however, causality is uncertain (Prod Info FLOLAN(R) intravenous injection, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) Epoprostenol therapy can inhibit platelet aggregation and may increase the risk of bleeding (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Anemia, thrombocytopenia, and pancytopenia were reported during postmarketing surveillance; however, causality is uncertain (Prod Info FLOLAN(R) intravenous injection, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing was reported in 42% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 2% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Flushing was reported in 23% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 0% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    2) WITH POISONING/EXPOSURE
    a) Flushing was associated with excessive doses of epoprostenol during clinical trials (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Eczema/rash/urticaria were reported in 25% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 4% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    C) SKIN ULCER
    1) WITH THERAPEUTIC USE
    a) Skin ulcer was reported in 39% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 24% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JAW PAIN
    1) WITH THERAPEUTIC USE
    a) Jaw pain was reported in 54% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 0% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Jaw pain was reported in 75% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 0% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 44% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 31% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    C) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Nonspecific musculoskeletal pain was reported in 35% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 15% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Nonspecific musculoskeletal pain was reported in 84% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 65% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Hyperthyroidism was reported during postmarketing surveillance; however, causality is uncertain (Prod Info FLOLAN(R) intravenous injection, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) SYSTEMIC INFECTION
    1) WITH THERAPEUTIC USE
    a) Chills/fever/sepsis/flu-like symptoms were reported in 25% of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) who received an average epoprostenol dose of 9.2 nanograms/kg/min at study end plus conventional therapy (n=52) compared with 11% of patients who received conventional therapy alone (n=54) in an 8- or 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).
    b) Chills/fever/sepsis/flu-like symptoms were reported in 13% of patients with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) with an average epoprostenol dose of 11.2 nanograms/kg/min at study end plus conventional therapy (n=56) compared with 11% of patients who received conventional therapy alone (n=55) in a 12-week, prospective, open-label, randomized trial (Prod Info FLOLAN(R) intravenous injection, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Epoprostenol is classified as FDA pregnancy category B. Although adequate and well-controlled studies have not been conducted on the effect of epoprostenol in pregnant women, animal studies have indicated no evidence of fetal harm following maternal administration of epoprostenol doses up to 4.8 times the recommended human dose. It is unknown if epoprostenol is excreted in human milk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, there was no evidence of fetal harm following maternal administration of epoprostenol doses up to 4.8 times the recommended human dose (Prod Info FLOLAN(R) intravenous injection, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Epoprostenol is classified as FDA pregnancy category B (Prod Info FLOLAN(R) intravenous injection, 2015).
    a) At the time of this review, adequate and well-controlled studies have not been conducted on the effect of epoprostenol during pregnancy. Administer epoprostenol during pregnancy only if clearly needed (Prod Info FLOLAN(R) intravenous injection, 2015).
    B) ANIMAL STUDIES
    1) In animal studies, there was no evidence of fetal harm following maternal administration of epoprostenol doses up to 4.8 times the recommended human dose (Prod Info FLOLAN(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether epoprostenol is excreted in human milk. Advise the nursing mother to either discontinue nursing or discontinue epoprostenol therapy, considering the mother's clinical need and the benefits of breastfeeding to the infant (Prod Info FLOLAN(R) intravenous injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal studies, there was no evidence of fertility impairment following maternal administration of epoprostenol doses up to 4.8 times the recommended human dose (Prod Info FLOLAN(R) intravenous injection, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, human carcinogenicity studies have not been conducted.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, human carcinogenicity studies have not been conducted.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, long-term animal carcinogenicity studies have not been conducted (Prod Info FLOLAN(R) intravenous injection, 2015).

Genotoxicity

    A) During animal studies, there was no evidence of mutagenicity according to a micronucleus test, the Ames test and a DNA elution test, although the significance of the results of these tests is unknown due to the instability of epoprostenol (Prod Info FLOLAN(R) intravenous injection, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor blood pressure frequently.
    B) Monitor for evidence of bleeding. Obtain a baseline CBC with differential in patients at risk for bleeding (eg, patients currently taking anticoagulants); repeat as indicated.
    C) Monitor ECG and institute continuous cardiac monitoring following a significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor blood pressure frequently.
    B) Monitor for evidence of bleeding. Obtain a baseline CBC with differential in patients at risk for bleeding (eg, patients currently taking anticoagulants); repeat as indicated.
    C) Monitor ECG and institute continuous cardiac monitoring following a significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: Acute toxic dose has not been established. One patient experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecific concentration). Following the discontinuation of epoprostenol, the patient regained consciousness within seconds.
    B) THERAPEUTIC DOSE: ADULTS: Initially, 2 ng/kg/min IV; may be titrated in 1 to 2 nanograms/kg/min increments at intervals of at least 15 minutes to allow for assessment of clinical response. PEDIATRIC: Safety and effectiveness have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial intravenous infusion is 2 nanograms/kg/min. The infusion may be titrated in 1 to 2 nanograms/kg/min increments at intervals of at least 15 minutes to allow for assessment of clinical response. Abrupt withdrawal or sudden large reductions in infusion rates should be avoided in order to prevent the occurrence of symptoms associated with rebound pulmonary hypertension (eg, dyspnea, dizziness, and asthenia) (Prod Info FLOLAN(R) intravenous injection, 2015).
    7.2.2) PEDIATRIC
    A) Safety and effectiveness have not been established in pediatric patients (Prod Info FLOLAN(R) intravenous injection, 2015).

Maximum Tolerated Exposure

    A) One patient with pulmonary arterial hypertension associated with scleroderma spectrum of diseases (PAH/SSD) experienced vomiting and became unconscious with an unrecordable blood pressure after receiving 50 mL of epoprostenol (unspecified concentration). Following the discontinuation of epoprostenol, the patient regained consciousness within seconds (Prod Info FLOLAN(R) intravenous injection, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Epoprostenol sodium is a naturally occurring prostaglandin and a known metabolite of arachidonic acid. It directly stimulates vasodilation of pulmonary and systemic arterial vascular beds, and inhibits platelet aggregation (Prod Info FLOLAN(R) intravenous injection, 2015).

Physicochemical

Physical Characteristics

    A) White or off-white powder (Prod Info FLOLAN(R) intravenous injection, 2015)

Molecular Weight

    A) 374.45 (Prod Info FLOLAN(R) intravenous injection, 2015)

References

General Bibliography

    1) Product Information: FLOLAN(R) intravenous injection, epoprostenol sodium intravenous injection. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2015.