Flolan (Epoprostenol Sodium)

FLOLAN®

Glaxo Wellcome

Epoprostenol Sodium

Vasodilator

Action And Clinical Pharmacology: Epoprostenol, also known as prostacyclin, PGl2 or PGX, a metabolite of arachidonic acid, is a naturally occurring prostaglandin. Epoprostenol has two major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects of epoprostenol 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.

Pharmacokinetics: Epoprostenol is rapidly hydrolyzed at neutral blood pH and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (93 mL/min/kg), 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; the in vivo half-life of epoprostenol in man is therefore 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, is 10.6 minutes in males (n=954) and 10.8 minutes in 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 6-keto-PGF1à (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1à (enzymatically formed), both of which have pharmacological activity at 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 man.

Pharmacodynamics: Acute i.v. infusions of epoprostenol for up to 15 minutes in patients with primary pulmonary hypertension (PPH) produced dose-related increases in cardiac index (Cl) 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) in patients with PPH were variable and minor.

Chronic hemodynamic effects were generally similar to acute effects. Cl, SV, and arterial oxygen saturation were increased, and PAPm, right atrial pressure (RAP), TPR, and systemic vascular resistance (SVR) were decreased in patients who received epoprostenol chronically, compared to those who did not.

Survival was improved in NYHA functional Class III and Class IV PPH patients treated with epoprostenol for 12 weeks in a multicenter, open, randomized, parallel, controlled study. At the end of the treatment period, 8 of 40 patients receiving standard therapy alone had died, whereas none of the 41 patients receiving epoprostenol had died (p=0.003).

Indications And Clinical Uses: For the long-term i.v. treatment of primary pulmonary hypertension (PPH) in NYHA functional Class III and Class IV patients.

Prior to initiation of therapy, the potential benefit of epoprostenol should be weighed against the risks associated with use of the drug and the presence of an indwelling central venous catheter.

Epoprostenol should be used only by clinicians experienced in the diagnosis and treatment of PPH. The diagnosis of PPH should be carefully established by standard clinical tests to exclude secondary causes of pulmonary hypertension.

Contra-Indications: The chronic use of epoprostenol in patients with congestive heart failure (CHF) due to severe left ventricular systolic dysfunction is contraindicated. A large study evaluating the effect of epoprostenol on survival in NYHA Class III and IV patients with CHF due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving epoprostenol plus standard therapy than in those receiving standard therapy alone.

Epoprostenol is also contraindicated in patients with known or suspected hypersensitivity to the drug or any of its excipients, or to structurally related compounds.

Manufacturers’ Warnings In Clinical States: Epoprostenol must be reconstituted only as directed using specific sterile diluent. Epoprostenol must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

Epoprostenol is not to be used for bolus administration (see Adverse Effects, Adverse Events During Acute Dose-Ranging).

Abrupt Withdrawal: Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of epoprostenol may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, there were rare reports of deaths considered attributable to the interruption of epoprostenol. Abrupt withdrawal should be avoided.

Pulmonary Edema: A minority of patients have PPH associated with pulmonary veno-occlusive disease. Some of these patients develop pulmonary edema during dose-ranging. Where pulmonary edema arises within hours to days of starting epoprostenol infusion, a diagnosis of veno-occlusive disease should be considered. In such cases consideration should be given to discontinuation of epoprostenol.

Epoprostenol should not be used chronically in patients who develop pulmonary edema during dose-ranging.

Sepsis: Sepsis is a known risk associated with the presence of an indwelling central venous catheter and requires immediate access to expert medical care (see Adverse Effects, Adverse Events Attributable to the Drug Delivery System).

Precautions: Epoprostenol is a potent pulmonary and systemic vasodilator. Acute dose-ranging with epoprostenol must be performed in a hospital setting with adequate personnel and equipment for physiologic monitoring and emergency care.

During the early phase of chronic administration, intense patient education is required.

Due to the potential for problems associated with the drug delivery system, immediate access to medical care should be available during chronic treatment.

Epoprostenol is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with epoprostenol requires commitment by the patient to drug reconstitution, drug administration, care of the permanent central venous catheter, and access to intense and ongoing patient education. Sterile technique must be adhered to in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of epoprostenol may result in rapid symptomatic deterioration. The decision to receive epoprostenol for PPH should be based upon the understanding that there is a high likelihood that therapy with epoprostenol will be needed for prolonged periods, possibly years, and the patient’s ability to accept and care for a permanent i.v. catheter and infusion pump should be carefully considered.

Based on clinical trials, the acute hemodynamic response to epoprostenol did not correlate well with survival during chronic use of epoprostenol. Dosage of epoprostenol during chronic use should be adjusted at the first sign of recurrence or worsening of symptoms attributable to PPH, or the occurrence of adverse events associated with epoprostenol (see Dosage). Following dosage adjustments, standing and supine blood pressure and heart rate should be monitored closely for several hours.

During ongoing treatment, patients should avoid situations which promote vasodilation such as saunas, hot baths and sunbathing. Severe hypotension has been seen in patients treated with chronic epoprostenol infusions under such circumstances.

Epoprostenol use has been associated with an increased incidence of bradycardia in patients with PPH and with episodes of severe hypotension, including fatalities.

Risk of Bleeding: Prothrombin times should be monitored because anticoagulant therapy is generally recommended in these patients. Platelet counts should also be monitored.

Drug Interactions: Additional reductions in blood pressure may occur when epoprostenol is administered with diuretics, antihypertensive agents or other vasodilators. When NSAIDs or other drugs affecting platelet aggregation are used concomitantly, there is the potential for epoprostenol to increase the risk of bleeding. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators and supplemental oxygen.

Pregnancy : There are no adequate and well-controlled studies in pregnant women.

Labor and Delivery: The use of epoprostenol during labor, vaginal delivery or caesarean section has not been adequately studied in humans.

Lactation: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, consideration should be given to discontinuation of breast feeding when epoprostenol is to be administered to a nursing woman.

Children: The safety and effectiveness of epoprostenol in children have not been established.

Geriatrics: Clinical studies of epoprostenol did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be made carefully, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Adverse Reactions: During clinical trials, adverse events were classified as follows: (1) adverse events during acute dose-ranging, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.

Adverse Events During Acute Dose-Ranging: During acute dose-ranging in clinical trials, epoprostenol was administered in 2 ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and those that limited further increases in dose were generally related to the major pharmacologic effect of epoprostenol, i.e., vasodilation. Table I lists the adverse events reported during acute dose-ranging in decreasing order of frequency as well as the % of cases where the event was dose limiting.

Adverse Events During Chronic Administration: Interpretation of adverse events is complicated by the clinical features of PPH, which may be similar to some of the pharmacologic effects of epoprostenol (e.g., dizziness, syncope). Adverse events probably related to the underlying disease include dyspnea, fatigue, chest pain, right ventricular failure and pallor. Several adverse events, on the other hand, can clearly be attributed to epoprostenol. These include jaw pain, flushing, headache, diarrhea, nausea and vomiting, flu-like symptoms and anxiety/nervousness. In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table III lists adverse events that occurred at a rate at least 10% different in the 2 groups in controlled trials.

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.

Although the number of patients was small, in controlled trials there was a trend towards increased incidence of bradycardia associated with chronic treatment in patients
Adverse Events Attributable to the Drug Delivery System: Chronic infusions of epoprostenol are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled trials of up to 12 weeks duration, 21% of patients reported a local infection and 13% of patients reported pain at the injection site. During subsequent long-term follow-up, sepsis was reported at least once in 14% of patients and occurred at a rate of 0.32 infections per patient per year in patients treated with epoprostenol. When suspected, sepsis should be diagnosed and treated quickly. It is therefore important that these patients have immediate access to expert medical care. Malfunctions in the delivery system resulting in an inadvertent bolus of, or a reduction in, epoprostenol were associated with symptoms related to excess or insufficient epoprostenol respectively, that may lead to serious consequences including death (see Warnings, Adverse Effects, Adverse Events During Chronic Administration and Overdose: Symptoms and Treatment).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Signs and symptoms of excessive doses of epoprostenol are the expected dose-limiting pharmacologic effects of epoprostenol including flushing, headache, hypotension, tachycardia, nausea, vomiting and diarrhea. Treatment will ordinarily require dose reduction of epoprostenol.

One patient with secondary pulmonary hypertension accidentally received 50 mL of an unspecified concentration of epoprostenol. The patient vomited and became unconscious with an initially unobtainable blood pressure. Epoprostenol was discontinued, and the patient regained consciousness within seconds.

Dosage And Administration: Epoprostenol must be reconstituted only with specific sterile diluent. Reconstituted solutions of epoprostenol must not be diluted or administered with other parenteral solutions or medications (see Warnings).

Epoprostenol is not to be used for bolus administration.

During acute dose-ranging, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, dose reduction should be considered, but such an increase does not imply that chronic treatment is contraindicated. However, in the rare occurrence of pulmonary edema, chronic treatment is contraindicated.

During chronic use, epoprostenol is delivered continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, anticoagulant therapy should be administered to PPH patients receiving epoprostenol to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. In order to reduce the risk of infection, aseptic technique must be used in the reconstitution and administration of epoprostenol as well as in routine catheter care. Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of epoprostenol may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. The decision to initiate therapy with epoprostenol should be based upon the understanding that there is a high likelihood that i.v. therapy with epoprostenol will be needed for prolonged periods, possibly years, and the patient’s ability to accept and care for a permanent i.v. catheter and infusion pump should be carefully considered.

Acute Dose-Ranging: The initial chronic infusion rate of epoprostenol is determined by an acute dose-ranging procedure. During controlled clinical trials, this procedure was performed during cardiac catheterization. The infusion rate is initiated at 2 ng/kg/min and increased in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited. The most common dose-limiting pharmacologic effects during dose-ranging are flushing, nausea, vomiting, headache, hypotension, chest pain, dizziness and bradycardia (see Adverse Effects, Adverse Events During Dose-Ranging). During acute dose-ranging in clinical trials, the mean maximum dose that did not elicit dose-limiting pharmacologic effects was 8.6±0.3 ng/kg/min.

Continuous Chronic Infusion: Chronic continuous infusion of epoprostenol should be administered through a central venous catheter. Temporary peripheral i.v. infusions may be used until central access is established. Chronic infusions of epoprostenol should be initiated at 4 ng/kg/min less than the maximum-tolerated infusion rate determined during acute dose-ranging. If the maximum-tolerated infusion rate is less than 5 ng/kg/min, the chronic infusion should be started at one-half the maximum-tolerated infusion rate. During clinical trials, the mean initial chronic infusion rate was 5 ng/kg/min.

Dosage Adjustments: Changes in the chronic infusion rate should be based on persistence, recurrence or worsening of the patient’s symptoms of PPH and the occurrence of adverse events due to excessive doses of epoprostenol. In general, the need for increases in dose from the initial chronic dose should be expected over time. In the controlled 12-week trial, for example, the dose increased from a mean starting dose of 5.2 ng/kg/min (4 ng/kg/min less than the new tolerated dose) to 9.2 ng/kg/min by the end of week 12, just 1.6 ng/kg/min less than the mean nontolerated dose in acute dose-ranging.

Increments in dose should be considered if symptoms of PPH persist or recur after improving. The infusion should be increased by 1 to 2 ng/kg/min increments at intervals sufficient to allow assessment of clinical response and tolerability; these intervals should be of at least 15 minutes. Following establishment of a new chronic infusion rate, the patient should be observed, and standing and supine blood pressure and heart rate monitored for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-related pharmacologic events similar to those observed during acute dose-ranging may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Dosage decreases should generally be made gradually in 2 ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Abrupt withdrawal of epoprostenol or sudden large reductions in infusion rates should be avoided. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), infusion rates of epoprostenol should be adjusted only under the direction of a physician.

In patients receiving lung transplants, doses of epoprostenol were tapered after the initiation of cardiopulmonary bypass.

Administration: Epoprostenol is administered by continuous i.v. infusion via a central venous catheter using an ambulatory infusion pump as recommended by the physician. During dose-ranging, epoprostenol may be administered peripherally.

The ambulatory infusion pump used to administer epoprostenol 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, (5) be positive pressure driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver epoprostenol, and (6) have design characteristics that minimize the likelihood of accidental bolus administration. The reservoir should be made of polyvinyl chloride, polypropylene, or glass.

To avoid potential interruptions in drug delivery, the patient should have access to a back-up infusion pump and additional i.v. infusion sets. A multilumen catheter should be considered if other i.v. therapies are routinely administered.

Preliminary data suggest that peristaltic pumps may have advantages over syringe pumps.

Prior to use, reconstituted solutions of epoprostenol must be protected from light and must be refrigerated at 2 to 8°C if not used immediately. Under these conditions, reconstituted epoprostenol solution may be stored for up to 24 hours before being transferred to the infusion pump. Reconstituted epoprostenol solution that has not been transferred to the infusion pump within 24 hours (i.e., that has been stored for more than 24 hours) is to be discarded. Do not freeze reconstituted solutions of epoprostenol.

Once placed in the pump, a single reservoir of reconstituted epoprostenol solution can be administered for up to 24 hours by maintaining the temperature between 2 to 8°C with the use of 2 frozen 170 mL gel packs in a cold pouch. The gel packs should be changed every 12 hours or every 8 hours if the ambient temperature approaches 30°C. When stored or in use, reconstituted epoprostenol must not be exposed to direct sunlight.

Reconstitution: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Epoprostenol is only stable when reconstituted with specific sterile diluent. Epoprostenol must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

A concentration for the solution of epoprostenol for acute dose-ranging or chronic therapy should be selected 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. Epoprostenol, when administered chronically, should be prepared in a drug delivery reservoir appropriate for the infusion pump with a total reservoir volume of at least 100 mL. Epoprostenol should be prepared using 2 vials of the specific sterile diluent for epoprostenol for use during a 24-hour period. Table V gives directions for preparing several different concentrations of epoprostenol.

Preparation of Reconstituted Solutions

Directions To Make 100 mL of Solution with Final Concentration of:

Dissolve contents of one 0.5 mg vial with 5 mL of sterile diluent . Withdraw 3 mL and add to sufficient sterile diluent to make a total of 100 mL. 3 000 ng/mL

Dissolve contents of one 0.5 mg vial with 5 mL of sterile diluent . Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 5 000 ng/mL

Dissolve contents of two 0.5 mg vials each with 5 mL of sterile diluent . Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 10 000 ng/mL

Dissolve contents of one 1.5 mg vial with 5 mL of sterile diluent . Withdraw entire vial contents and add sufficient sterile diluent to make a total of 100 mL. 15 000 ng/mL

Infusion Rates During Acute Dose-Ranging: More than one solution strength may be required to accommodate the range of infusions anticipated during acute dose-ranging. Generally, 3 000 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:

Availability And Storage: Each vial of sterile, freeze-dried powder contains: epoprostenol sodium equivalent to epoprostenol 0.5 mg (500 000 ng) or 1.5 mg (1 500 000 ng). Nonmedicinal ingredients: glycine, mannitol, sodium chloride and sodium hydroxide (added to adjust pH). Flint glass vials, individually packaged in a carton. Store at 15 to 25°C. Protect from light.

Each vial of sterile diluent contains: glycine 94 mg, sodium chloride 73.3 mg, sodium hydroxide (added to adjust pH) and water for injection USP q.s. to 50 mL. Glass vials of 50 mL, trays of 2. Store at 15 to 25°C. Do not freeze.

FLOLAN® Glaxo Wellcome Epoprostenol Sodium Vasodilator

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