Flolan Information
Flolan (Epoprostenol na) Description
Flolan (Epoprostenol na) (epoprostenol sodium) for Injection is a sterile sodium salt formulated for intravenous (IV) administration. Each vial of Flolan (Epoprostenol na) contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.
Epoprostenol (PGI, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation.
Epoprostenol is (5Z,9α,11α,13,15)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid.
Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of CHNaO. The structural formula is:
Flolan (Epoprostenol na) is a white to off-white powder that must be reconstituted with STERILE DILUENT for Flolan (Epoprostenol na) . STERILE DILUENT for Flolan (Epoprostenol na) is supplied in glass vials containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection, USP.
The reconstituted solution of Flolan (Epoprostenol na) has a pH of 10.2 to 10.8 and is increasingly unstable at a lower pH.
Flolan (Epoprostenol na) Clinical Pharmacology
Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. 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.
No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. 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. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n = 954) and females (n = 1,024).
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-PGF (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF (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.
Flolan (Epoprostenol na) Indications And Usage
Flolan (Epoprostenol na) is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.
Flolan (Epoprostenol na) Contraindications
A large study evaluating the effect of Flolan (Epoprostenol na) on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving Flolan (Epoprostenol na) plus conventional therapy than in those receiving conventional therapy alone. The chronic use of Flolan (Epoprostenol na) in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.
Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Flolan (Epoprostenol na) should not be used chronically in patients who develop pulmonary edema during dose initiation.
Flolan (Epoprostenol na) is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.
Flolan (Epoprostenol na) Warnings
Flolan (Epoprostenol na) must be reconstituted only as directed using STERILE DILUENT for Flolan (Epoprostenol na) . Flolan (Epoprostenol na) must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
Flolan (Epoprostenol na) Precautions
Flolan (Epoprostenol na) should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. Carefully establish the diagnosis of idiopathic or heritable PAH or PAH/CTD.
Flolan (Epoprostenol na) is a potent pulmonary and systemic vasodilator. Initiate Flolan (Epoprostenol na) in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.
Flolan (Epoprostenol na) is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding (see PRECAUTIONS: Drug Interactions).
During chronic use, deliver Flolan (Epoprostenol na) continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving Flolan (Epoprostenol na) to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of Flolan (Epoprostenol na) and in routine catheter care. Because Flolan (Epoprostenol na) is metabolized rapidly, even brief interruptions in the delivery of Flolan (Epoprostenol na) may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with Flolan (Epoprostenol na) will likely be needed for prolonged periods, possibly years, so consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump.
Based on clinical trials, the acute hemodynamic response to Flolan (Epoprostenol na) did not correlate well with improvement in exercise tolerance or survival during chronic use of Flolan (Epoprostenol na) . Adjust dosage of Flolan (Epoprostenol na) during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with Flolan (Epoprostenol na) (see DOSAGE AND ADMINISTRATION). Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.
Additional reductions in blood pressure may occur when Flolan (Epoprostenol na) is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for Flolan (Epoprostenol na) to increase the risk of bleeding. However, patients receiving infusions of Flolan (Epoprostenol na) in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, Flolan (Epoprostenol na) was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.
In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with Flolan (Epoprostenol na) was initiated, apparent oral clearance values for furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the second day of therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be clinically significant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with Flolan (Epoprostenol na) , which may be clinically significant in patients prone to digoxin toxicity.
Flolan (Epoprostenol na) Adverse Reactions
During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.
In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 4 lists adverse events that occurred at a rate at least 10% greater on Flolan (Epoprostenol na) in controlled trials.
Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving Flolan (Epoprostenol na) .
In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% greater on Flolan (Epoprostenol na) in the controlled trial.
Although the relationship to Flolan (Epoprostenol na) administration has not been established, pulmonary embolism has been reported in several patients taking Flolan (Epoprostenol na) and there have been reports of hepatic failure.
Flolan (Epoprostenol na) Overdosage
Signs and symptoms of excessive doses of Flolan (Epoprostenol na) during clinical trials are the expected dose-limiting pharmacologic effects of Flolan (Epoprostenol na) , including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of Flolan (Epoprostenol na) .
One patient with PAH/CTD accidentally received 50 mL of an unspecified concentration of Flolan (Epoprostenol na) . The patient vomited and became unconscious with an initially unrecordable blood pressure. Flolan (Epoprostenol na) was discontinued and the patient regained consciousness within seconds. In clinical practice, fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of Flolan (Epoprostenol na) .
Single intravenous doses of Flolan (Epoprostenol na) at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia.
Flolan (Epoprostenol na) Dosage And Administration
Flolan (Epoprostenol na) must be reconstituted only with STERILE DILUENT for Flolan (Epoprostenol na) .
Administer continuous chronic infusion of Flolan (Epoprostenol na) through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of Flolan (Epoprostenol na) at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then decrease the infusion rate until Flolan (Epoprostenol na) is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, identify a lower dose that is tolerated by the patient.
In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.
Flolan (Epoprostenol na) is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, Flolan (Epoprostenol na) may be administered peripherally.
The ambulatory infusion pump used to administer Flolan (Epoprostenol na) should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Flolan (Epoprostenol na) . The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.
To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.
To facilitate extended use at ambient temperatures exceeding 25°C (77°F), a cold pouch with frozen gel packs was used in clinical trials (see DOSAGE AND ADMINISTRATION: Storage and Stability). The cold pouches and gel packs used in clinical trials were obtained from Palco Labs, Palo Alto, California. Any cold pouch used must be capable of maintaining the temperature of reconstituted Flolan (Epoprostenol na) between 2° and 8°C for 12 hours.
Flolan (Epoprostenol na) is stable only when reconstituted with STERILE DILUENT for Flolan (Epoprostenol na) . Flolan (Epoprostenol na) must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.
Select a concentration for the solution of Flolan (Epoprostenol na) that is compatible with the infusion pump being used with respect to minimum and maximum flow rates, reservoir capacity, and the infusion pump criteria listed above. When administered chronically, prepare Flolan (Epoprostenol na) in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL, using 2 vials of STERILE DILUENT for Flolan (Epoprostenol na) for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of Flolan (Epoprostenol na) .
*
Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Infusion rates may be calculated using the following formula:
Final Concentration (ng/mL)
Tables 7 through 10 provide infusion delivery rates for doses up to 16 ng/kg/min based upon patient weight, drug delivery rate, and concentration of the solution of Flolan (Epoprostenol na) to be used. These tables may be used to select the most appropriate concentration of Flolan (Epoprostenol na) that will result in an infusion rate between the minimum and maximum flow rates of the infusion pump and that will allow the desired duration of infusion from a given reservoir volume. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long-term administration of Flolan (Epoprostenol na) .
Unopened vials of Flolan (Epoprostenol na) are stable until the date indicated on the package when stored at 15° to 25°C (59° to 77°F) and protected from light in the carton. Unopened vials of STERILE DILUENT for Flolan (Epoprostenol na) are stable until the date indicated on the package when stored at 15° to 25°C (59° to 77°F).
Prior to use, reconstituted solutions of Flolan (Epoprostenol na) must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately.
During use, a single reservoir of reconstituted solution of Flolan (Epoprostenol na) can be administered at room temperature for a total duration of 8 hours, or it can be used with a cold pouch and administered up to 24 hours with the use of 2 frozen 6-oz gel packs in a cold pouch. When stored or in use, insulate reconstituted Flolan (Epoprostenol na) from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.
Flolan (Epoprostenol na) How Supplied
Flolan (Epoprostenol na) for Injection is supplied as a sterile freeze-dried powder in 17-mL flint glass vials with gray butyl rubber closures, individually packaged in a carton.
17-mL vial containing epoprostenol sodium equivalent to 0.5 mg (500,000 ng), carton of 1 (NDC 0173-0517-00).
17-mL vial containing epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng), carton of 1 (NDC 0173-0519-00).
The STERILE DILUENT for Flolan (Epoprostenol na) is supplied in flint glass vials containing 50-mL diluent with fluororesin-faced butyl rubber closures.
50-mL of STERILE DILUENT for Flolan (Epoprostenol na) , tray of 2 vials (NDC 0173-0518-01).
GlaxoSmithKline
Research Triangle Park, NC 27709
©2011, GlaxoSmithKline. All rights reserved.
March 2011
FLL:2PI
Flolan (Epoprostenol na) Principal Display Panel
Each vial contains epoprostenol sodium equivalent to 0.5 mg (500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.
See package insert for Dosage and Administration.
Store at 15 and 25 C (59 to 77F).
Protect from light.
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in Italy
10000000025562
Rev. 2/06
Flolan (Epoprostenol na) Principal Display Panel
Each vial contains epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.
See package insert for Dosage and Administration.
Store at 15 and 25 C (59 to 77F).
Protect from light.
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in Italy
10000000024890
Rev. 1/06
Flolan (Epoprostenol na) Principal Display Panel
Each vial contains 94 mg glycine, ,73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and water for Injection, USP.
For reconstitution information see package insert for Flolan (Epoprostenol na) (epoprostenol sodium) for Injection.
Store at 15 to 25C (59 to 77F).
GlaxoSmithKline
Research Triangle Park, NC 27709
Made in England
10000000023966 Rev. 1/06
