Epoprostenol sodium (Flolan)
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Epoprostenol sodium (Flolan)

FLOLAN®
(epoprostenol sodium) for Injection

DRUG DESCRIPTION

FLOLAN (epoprostenol sodium) for Injection is a sterile sodium salt formulated for intravenous (IV) administration. Each vial of FLOLAN (epoprostenol sodium) 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 (PGI2, 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,13E,15S)-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 C20H31NaO5. The structural formula is:

FLOLAN® (epoprostenol sodium) Structural Formula Illustration

FLOLAN (epoprostenol sodium) is a white to off-white powder that must be reconstituted with STERILE DILUENT for FLOLAN (epoprostenol sodium) . STERILE DILUENT for FLOLAN (epoprostenol sodium) 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 sodium) has a pH of 10.2 to 10.8 and is increasingly unstable at a lower pH.

What are the possible side effects of epoprostenol (Flolan, Veletri)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • fever, flu symptoms, mouth and throat ulcers, rapid heart rate, rapid and shallow breathing, fainting;
  • chest pain, trouble breathing;
  • fast, slow, or uneven heart rate;
  • pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • blood in your...

Read All Potential Side Effects and See Pictures of Flolan »

What are the precautions when taking epoprostenol sodium (Flolan)?

Before using epoprostenol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart failure (on the left side of the heart), bleeding problems (such as bleeding of the stomach/intestines), blood disorders (such as thrombocytopenia), liver disease.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

To lower your risk of dizziness and lightheadedness, get...

Read All Potential Precautions of Flolan »

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

FLOLAN (epoprostenol sodium) is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) 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.

DOSAGE AND ADMINISTRATION

Important Note: FLOLAN (epoprostenol sodium) must be reconstituted only with STERILE DILUENT for FLOLAN (epoprostenol sodium) . Do not dilute reconstituted solutions of FLOLAN (epoprostenol sodium) or administer with other parenteral solutions or medications (see WARNINGS).

Dosage

Administer continuous chronic infusion of FLOLAN (epoprostenol sodium) through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of FLOLAN (epoprostenol sodium) 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 sodium) 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.

Dosage Adjustments

Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of FLOLAN (epoprostenol sodium) . In general, expect increases in dose from the initial chronic dose.

Consider increments in dose if symptoms of PAH persist or recur. Increase the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of FLOLAN (epoprostenol sodium) or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of FLOLAN (epoprostenol sodium) only under the direction of a physician.

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

Administration

FLOLAN (epoprostenol sodium) is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, FLOLAN (epoprostenol sodium) may be administered peripherally.

The ambulatory infusion pump used to administer FLOLAN (epoprostenol sodium) 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 sodium) . 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 sodium) between 2° and 8°C for 12 hours.

Reconstitution

FLOLAN (epoprostenol sodium) is stable only when reconstituted with STERILE DILUENT for FLOLAN (epoprostenol sodium) . FLOLAN (epoprostenol sodium) 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 sodium) 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 sodium) 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 sodium) for use during a 24-hour period. Table 6 gives directions for preparing several different concentrations of FLOLAN (epoprostenol sodium) .

Table 6: Reconstitution and Dilution Instructions

To make 100 mL of solution with Final Concentration (ng/mL) of: Directions:
3,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of STERILE DILUENT for FLOLAN. Withdraw 3 mL and add to sufficient STERILE DILUENT for FLOLAN to make a total of 100 mL.
5,000 ng/mL Dissolve contents of one 0.5-mg vial with 5 mL of STERILE DILUENT for FLOLAN. Withdraw entire vial contents and add sufficient STERILE DILUENT for FLOLAN to make a total of 100 mL.
10,000 ng/mL Dissolve contents of two 0.5-mg vials each with 5 mL of STERILE DILUENT for FLOLAN. Withdraw entire vial contents and add sufficient STERILE DILUENT for FLOLAN to make a total of 100 mL.
15,000 ng/mL* Dissolve contents of one 1.5-mg vial with 5 mL of STERILE DILUENT for FLOLAN. Withdraw entire vial contents and add sufficient STERILE DILUENT for FLOLAN to make a total of 100 mL.
* Higher concentrations may be required for patients who receive FLOLAN long-term.

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:

Infusion Rate (mL/hr) = [Dose (ng/kg/min) x Weight (kg) x 60 min/hr]/ 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 sodium) to be used. These tables may be used to select the most appropriate concentration of FLOLAN (epoprostenol sodium) 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 sodium) .

Table 7: Infusion Rates for FLOLAN (epoprostenol sodium) at a Concentration of 3,000 ng/Ml

Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min)
2 4 6 8 10 12 14 16
Infusion Delivery Rate (mL/h)
10 - - 1.2 1.6 2.0 2.4 2.8 3.2
20 - 1.6 2.4 3.2 4.0 4.8 5.6 6.4
30 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6
40 1.6 3.2 4.8 6.4 8.0 9.6 11.2 12.8
50 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0
60 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2
70 2.8 5.6 8.4 11.2 14.0 16.8 19.6 22.4
80 3.2 6.4 9.6 12.8 16.0 19.2 22.4 25.6
90 3.6 7.2 10.8 14.4 18.0 21.6 25.2 28.8
100 4.0 8.0 12.0 16.0 20.0 24.0 28.0 32.0

Table 8: Infusion Rates for FLOLAN (epoprostenol sodium) at a Concentration of 5,000 ng/mL

Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min)
2 4 6 8 10 12 14 16
Infusion Delivery Rate (mL/h)
10 - - - 1.0 1.2 1.4 1.7 1.9
20 - 1.0 1.4 1.9 2.4 2.9 3.4 3.8
30 - 1.4 2.2 2.9 3.6 4.3 5.0 5.8
40 1.0 1.9 2.9 3.8 4.8 5.8 6.7 7.7
50 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6
60 1.4 2.9 4.3 5.8 7.2 8.6 10.1 11.5
70 1.7 3.4 5.0 6.7 8.4 10.1 11.8 13.4
80 1.9 3.8 5.8 7.7 9.6 11.5 13.4 15.4
90 2.2 4.3 6.5 8.6 10.8 13.0 15.1 17.3
100 2.4 4.8 7.2 9.6 12.0 14.4 16.8 19.2

Table 9: Infusion Rates for FLOLAN (epoprostenol sodium) at a Concentration of 10,000 ng/mL

Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min)
4 6 8 10 12 14 16
Infusion Delivery Rate (mL/h)
20 - - 1.0 1.2 1.4 1.7 1.9
30 - 1.1 1.4 1.8 2.2 2.5 2.9
40 1.0 1.4 1.9 2.4 2.9 3.4 3.8
50 1.2 1.8 2.4 3.0 3.6 4.2 4.8
60 1.4 2.2 2.9 3.6 4.3 5.0 5.8
70 1.7 2.5 3.4 4.2 5.0 5.9 6.7
80 1.9 2.9 3.8 4.8 5.8 6.7 7.7
90 2.2 3.2 4.3 5.4 6.5 7.6 8.6
100 2.4 3.6 4.8 6.0 7.2 8.4 9.6

Table 10: Infusion Rates for FLOLAN (epoprostenol sodium) at a Concentration of 15,000 ng/mL

Patient Weight (kg) Dose or Drug Delivery Rate (ng/kg/min)
4 6 8 10 12 14 16
Infusion Delivery Rate (mL/h)
30 - - 1.0 1.2 1.4 1.7 1.9
40 - 1.0 1.3 1.6 1.9 2.2 2.6
50 - 1.2 1.6 2.0 2.4 2.8 3.2
60 1.0 1.4 1.9 2.4 2.9 3.4 3.8
70 1.1 1.7 2.2 2.8 3.4 3.9 4.5
80 1.3 1.9 2.6 3.2 3.8 4.5 5.1
90 1.4 2.2 2.9 3.6 4.3 5.0 5.8
100 1.6 2.4 3.2 4.0 4.8 5.6 6.4

Storage and Stability

Unopened vials of FLOLAN (epoprostenol sodium) 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 sodium) 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 sodium) must be protected from light and must be refrigerated at 2° to 8°C (36° to 46°F) if not used immediately. Do not freeze reconstituted solutions of FLOLAN (epoprostenol sodium) . Discard any reconstituted solution that has been frozen. Discard any reconstituted solution if it has been refrigerated for more than 48 hours.

During use, a single reservoir of reconstituted solution of FLOLAN (epoprostenol sodium) 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 sodium) from temperatures greater than 25°C (77°F) and less than 0°C (32°F), and do not expose to direct sunlight.

Use at Room Temperature

Prior to use at room temperature, 15° to 25°C (59° to 77°F), reconstituted solutions of FLOLAN (epoprostenol sodium) may be stored refrigerated at 2° to 8°C (36° to 46°F) for no longer than 40 hours. When administered at room temperature, reconstituted solutions may be used for no longer than 8 hours. This 48-hour period allows the patient to reconstitute a 2-day supply (200 mL) of FLOLAN (epoprostenol sodium) . Each 100-mL daily supply may be divided into 3 equal portions. Two of the portions are stored refrigerated at 2° to 8°C (36° to 46°F) until they are used.

Use with a Cold Pouch

Prior to infusion with the use of a cold pouch, solutions may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours. When a cold pouch is employed during the infusion, reconstituted solutions of FLOLAN (epoprostenol sodium) may be used for no longer than 24 hours. Change gel packs every 12 hours. Reconstituted solutions may be kept at 2° to 8°C (36° to 46°F), either in refrigerated storage or in a cold pouch or a combination of the two, for no more than 48 hours.

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not administer.

HOW SUPPLIED

FLOLAN (epoprostenol sodium) 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).

Store the vials of FLOLAN (epoprostenol sodium) at 15° to 25°C (59° to 77°F). Protect from light.

The STERILE DILUENT for FLOLAN (epoprostenol sodium) is supplied in flint glass vials containing 50-mL diluent with fluororesin-faced butyl rubber closures.

50-mL of STERILE DILUENT for FLOLAN (epoprostenol sodium) , tray of 2 vials (NDC 0173-0518-01).

Store the vials of STERILE DILUENT for FLOLAN (epoprostenol sodium) at 15° to 25°C (59° to 77°F). DO NOT FREEZE.

GlaxoSmithKline, Research Triangle Park, NC 27709. March 2011

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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.

Adverse Events During Dose Initiation and Escalation

During early clinical trials, FLOLAN (epoprostenol sodium) was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of FLOLAN (epoprostenol sodium) . The most common dose-limiting adverse events (occurring in ≥ 1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 3 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.

Table 3: Adverse Events During Dose Initiation and Escalation

Adverse Events Occurring in ≥ 1% of Patients FLOLAN
(n = 391)
Flushing 58%
Headache 49%
Nausea/vomiting 32%
Hypotension 16%
Anxiety, nervousness, agitation 11%
Chest pain 11%
Dizziness 8%
Bradycardia 5%
Abdominal pain 5%
Musculoskeletal pain 3%
Dyspnea 2%
Back pain 2%
Sweating 1%
Dyspepsia 1%
Hypesthesia/paresthesia 1%
Tachycardia 1%

Adverse Events During Chronic Administration

Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of FLOLAN (epoprostenol sodium) (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to FLOLAN (epoprostenol sodium) . These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during FLOLAN (epoprostenol sodium) therapy, and a role for the drug in these events cannot be excluded.

Adverse Events During Chronic Administration for Idiopathic or Heritable PAH

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 sodium) in controlled trials.

Table 4: Adverse Events Regardless of Attribution Occurring in Patients With Idiopathic or Heritable PAH With ≥ 10% Difference Between FLOLAN (epoprostenol sodium) and Conventional Therapy Alone

Adverse Event FLOLAN
(n = 52)
Conventional Therapy
(n = 54)
Occurrence More Common With FLOLAN
General
  Chills/fever/sepsis/flu-like symptoms 25% 11%
Cardiovascular
  Tachycardia 35% 24%
  Flushing 42% 2%
Gastrointestinal
  Diarrhea 37% 6%
  Nausea/vomiting 67% 48%
Musculoskeletal
  Jaw pain 54% 0%
  Myalgia 44% 31%
  Nonspecific musculoskeletal pain 35% 15%
Neurological
  Anxiety/nervousness/tremor 21% 9%
  Dizziness 83% 70%
  Headache 83% 33%
  Hypesthesia, hyperesthesia, paresthesia 12% 2%

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving FLOLAN (epoprostenol sodium) .

Adverse Events During Chronic Administration for PAH/SSD

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 sodium) in the controlled trial.

Table 5: Adverse Events Regardless of Attribution Occurring in Patients with PAH/SSD With ≥ 10% Difference Between FLOLAN (epoprostenol sodium) and Conventional Therapy Alone

Adverse Event FLOLAN
(n = 56)
Conventional Therapy
(n = 55)
Occurrence More Common With FLOLAN
Cardiovascular
  Flushing 23% 0%
  Hypotension 13% 0%
Gastrointestinal
  Anorexia 66% 47%
  Nausea/vomiting 41% 16%
  Diarrhea 50% 5%
Musculoskeletal
  Jaw pain 75% 0%
  Pain/neck pain/arthralgia 84% 65%
Neurological
  Headache 46% 5%
Skin and Appendages
  Skin ulcer 39% 24%
  Eczema/rash/urticaria 25% 4%

Although the relationship to FLOLAN (epoprostenol sodium) administration has not been established, pulmonary embolism has been reported in several patients taking FLOLAN (epoprostenol sodium) and there have been reports of hepatic failure.

Adverse Events Attributable to the Drug Delivery System

Chronic infusions of FLOLAN (epoprostenol sodium) are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks' duration, the local infection rate was about 18%, and the rate for pain was about 11%. During long-term follow-up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with FLOLAN (epoprostenol sodium) . This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in FLOLAN (epoprostenol sodium) were associated with symptoms related to excess or insufficient FLOLAN (epoprostenol sodium) , respectively (see ADVERSE REACTIONS: Adverse Events During Chronic Administration).

Observed During Clinical Practice

In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of FLOLAN (epoprostenol sodium) . Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to FLOLAN (epoprostenol sodium) .

Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly.

Endocrine and Metabolic: Hyperthyroidism.

Read the Flolan (epoprostenol sodium) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Additional reductions in blood pressure may occur when FLOLAN (epoprostenol sodium) 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 sodium) to increase the risk of bleeding. However, patients receiving infusions of FLOLAN (epoprostenol sodium) in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, FLOLAN (epoprostenol sodium) 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 sodium) 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 sodium) , which may be clinically significant in patients prone to digoxin toxicity.

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

FLOLAN (epoprostenol sodium) must be reconstituted only as directed using STERILE DILUENT for FLOLAN (epoprostenol sodium) . FLOLAN (epoprostenol sodium) must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

Abrupt Withdrawal

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of FLOLAN (epoprostenol sodium) may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III patient's death was judged attributable to the interruption of FLOLAN (epoprostenol sodium) . Avoid abrupt withdrawal.

Sepsis

See ADVERSE REACTIONS: Adverse Events Attributable to the Drug Delivery System.

PRECAUTIONS

General

FLOLAN (epoprostenol sodium) 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 sodium) is a potent pulmonary and systemic vasodilator. Initiate FLOLAN (epoprostenol sodium) 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 sodium) 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 sodium) continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving FLOLAN (epoprostenol sodium) 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 sodium) and in routine catheter care. Because FLOLAN (epoprostenol sodium) is metabolized rapidly, even brief interruptions in the delivery of FLOLAN (epoprostenol sodium) may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with FLOLAN (epoprostenol sodium) 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 sodium) did not correlate well with improvement in exercise tolerance or survival during chronic use of FLOLAN (epoprostenol sodium) . Adjust dosage of FLOLAN (epoprostenol sodium) 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 (see DOSAGE AND ADMINISTRATION). Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were also negative, although the instability of epoprostenol makes the significance of these tests uncertain. Fertility was not impaired in rats given FLOLAN (epoprostenol sodium) by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m²/day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m²/day, IV] based on body surface area).

Pregnancy

Pregnancy Category B

Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100 mcg/kg/day (600 mcg/m²/day in rats, 2.5 times the recommended human dose, and 1,180 mcg/m²/day in rabbits, 4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to FLOLAN (epoprostenol sodium) . There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

The use of FLOLAN (epoprostenol sodium) during labor, vaginal delivery, or cesarean section has not been adequately studied in humans.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FLOLAN (epoprostenol sodium) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of FLOLAN (epoprostenol sodium) in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Signs and symptoms of excessive doses of FLOLAN (epoprostenol sodium) during clinical trials are the expected dose-limiting pharmacologic effects of FLOLAN (epoprostenol sodium) , including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of FLOLAN (epoprostenol sodium) .

One patient with PAH/CTD accidentally received 50 mL of an unspecified concentration of FLOLAN (epoprostenol sodium) . The patient vomited and became unconscious with an initially unrecordable blood pressure. FLOLAN (epoprostenol sodium) 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 sodium) .

Single intravenous doses of FLOLAN (epoprostenol sodium) 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.

CONTRAINDICATIONS

A large study evaluating the effect of FLOLAN (epoprostenol sodium) 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 sodium) plus conventional therapy than in those receiving conventional therapy alone. The chronic use of FLOLAN (epoprostenol sodium) 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 sodium) should not be used chronically in patients who develop pulmonary edema during dose initiation.

FLOLAN (epoprostenol sodium) is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

General

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

Pharmacokinetics

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-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.

Clinical Trials In Pulmonary Arterial Hypertension (Pah)

Acute Hemodynamic Effects

Acute intravenous infusions of FLOLAN (epoprostenol sodium) for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (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 FLOLAN (epoprostenol sodium) on mean pulmonary artery pressure (PAPm) were variable and minor.

Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects: Chronic continuous infusions of FLOLAN (epoprostenol sodium) in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks' duration comparing FLOLAN (epoprostenol sodium) plus conventional therapy to conventional therapy alone. Dosage of FLOLAN (epoprostenol sodium) was determined as described in DOSAGE AND ADMINISTRATION and averaged 9.2 ng/kg/min at study's end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described.

Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received FLOLAN (epoprostenol sodium) chronically compared to those who did not. Table 1 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment.

Table 1: Hemodynamics During Chronic Administration of FLOLAN (epoprostenol sodium) in Patients With Idiopathic or Heritable PAH

Hemodynamic Parameter Baseline Mean Change from Baselineat End of Treatment Period*
FLOLAN
(N = 52)
Standard Therapy
(N = 54)
FLOLAN
(N = 48)
Standard Therapy
(N = 41)
CI (L/min/m²) 2.0 2.0 0.3† -0.1
PAPm (mm Hg) 60 60 -5† 1
PVR (Wood U) 16 17 -4† 1
SAPm (mm Hg) 89 91 -4 -3
SV (mL/beat) 44 43 6† -1
PR (Wood U) 20 21 -5† 1
* At 8 weeks: FLOLAN (epoprostenol sodium) N = 10, conventional therapy N = 11 (N is the number of patients with hemodynamic data).
At 12 weeks: FLOLAN (epoprostenol sodium) N = 38, conventional therapy N = 30 (N is the number of patients with hemodynamic data).
† Denotes statistically significant difference between FLOLAN (epoprostenol sodium) and conventional therapy groups.
CI = cardiac index, PAPm = mean pulmonary arterial pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure, SV = stroke volume, TPR = total pulmonary resistance.

These hemodynamic improvements appeared to persist when FLOLAN (epoprostenol sodium) was administered for at least 36 months in an open, nonrandomized study.

Clinical Effects: Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous FLOLAN (epoprostenol sodium) plus conventional therapy (N = 52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N = 54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index.

Survival was improved in NYHA functional Class III and Class IV patients with idiopathic or heritable PAH treated with FLOLAN (epoprostenol sodium) for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving FLOLAN (epoprostenol sodium) died (p = 0.003).

Chronic Infusion in PAH/Scleroderma Spectrum of Diseases (SSD)

Hemodynamic Effects: Chronic continuous infusions of FLOLAN (epoprostenol sodium) in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks' duration comparing FLOLAN (epoprostenol sodium) plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of FLOLAN was determined as described in DOSAGE AND ADMINISTRATION and averaged 11.2 ng/kg/min at study's end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received FLOLAN (epoprostenol sodium) chronically compared to those who did not. Table 2 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.

Table 2: Hemodynamics During Chronic Administration of FLOLAN (epoprostenol sodium) in Patients With PAH/SSD

Hemodynamic Parameter Baseline Mean Change from Baselineat 12 Weeks
FLOLAN
(N = 56)
Conventional Therapy
(N = 55)
FLOLAN
(N = 50)
Conventional Therapy
(N = 48)
CI (L/min/m²) 1.9 2.2 0.5* -0.1
PAPm (mm Hg) 51 49 -5* 1
RAPm (mm Hg) 13 11 -1* 1
PVR (Wood U) 14 11 -5* 1
SAPm (mm Hg) 93 89 -8* -1
* Denotes statistically significant difference between FLOLAN (epoprostenol sodium) and conventional therapy groups (N is the number of patients with hemodynamic data).
CI = cardiac index, PAPm = mean pulmonary arterial pressure, RAPm = mean right arterial pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure.

Clinical Effects: Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous FLOLAN (epoprostenol sodium) plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with FLOLAN (epoprostenol sodium) compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with FLOLAN (epoprostenol sodium) and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with FLOLAN (epoprostenol sodium) and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12 weeks were not available for 5 patients treated with FLOLAN (epoprostenol sodium) and 7 patients treated with conventional therapy alone.

No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with FLOLAN (epoprostenol sodium) as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving FLOLAN (epoprostenol sodium) died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.

No controlled clinical trials with FLOLAN (epoprostenol sodium) have been performed in patients with pulmonary hypertension associated with other diseases.

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Patients receiving FLOLAN (epoprostenol sodium) should receive the following information. FLOLAN (epoprostenol sodium) must be reconstituted only with STERILE DILUENT for FLOLAN (epoprostenol sodium) . FLOLAN (epoprostenol sodium) is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with FLOLAN (epoprostenol sodium) requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of FLOLAN (epoprostenol sodium) may result in rapid symptomatic deterioration. A patient's decision to receive FLOLAN (epoprostenol sodium) should be based upon the understanding that there is a high likelihood that therapy with FLOLAN (epoprostenol sodium) will be needed for prolonged periods, possibly years. The patient's ability to accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Patients receiving FLOLAN (epoprostenol sodium) should receive the following information. FLOLAN (epoprostenol sodium) must be reconstituted only with STERILE DILUENT for FLOLAN (epoprostenol sodium) . FLOLAN (epoprostenol sodium) is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with FLOLAN (epoprostenol sodium) requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of FLOLAN (epoprostenol sodium) may result in rapid symptomatic deterioration. A patient's decision to receive FLOLAN (epoprostenol sodium) should be based upon the understanding that there is a high likelihood that therapy with FLOLAN (epoprostenol sodium) will be needed for prolonged periods, possibly years. The patient's ability to accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.

Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Flolan Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

EPOPROSTENOL - INJECTION

(E-poe-PROST-en-ol)

COMMON BRAND NAME(S): Flolan

USES: This medication is used to treat high blood pressure in the lungs (pulmonary arterial hypertension). It helps to increase your ability to exercise and improve symptoms such as shortness of breath and tiredness. It works by relaxing and widening the blood vessels (arteries) in the lungs and other parts of the body so that blood can flow more easily. This medication belongs to a class of drugs known as vasodilators.

HOW TO USE: When you first start using this medication, it must be given by a health care professional in a hospital or clinic. This medication is given as a continuous injection into the vein using an infusion pump, or as directed by your doctor.

Follow all instructions from your health care professional about how to properly use and prepare this medication and the infusion pump. Learn how to properly care for your injection site and how to avoid infection. Also learn how to store and discard needles and medical supplies safely. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid, and contact your health care professional immediately. If you have any questions about the use of this medication or the infusion pump, consult your health care professional.

Do not suddenly decrease the dose or suddenly stop using this medication because doing either may lead to serious (rarely fatal) worsening of your condition. If you must stop this medication, gradually reduce the dose as directed by your doctor. Consult your doctor immediately if your infusion is interrupted or if you develop worsening trouble breathing, dizziness, or weakness. To avoid interruptions in drug treatment, you should have a backup infusion pump and infusion sets available in case your equipment fails. Consult your health care professional for more information.

The dosage is based on your medical condition, weight, and response to treatment. Your doctor may also direct you to use additional medications to treat your condition and prevent problems. Use all prescribed medications exactly as directed.

Tell your doctor if your condition does not improve or if it worsens.

Disclaimer

Flolan Consumer (continued)

SIDE EFFECTS: Nausea, vomiting, diarrhea, dizziness, headache, flushing, sweating, abdominal pain, jaw pain, muscle/joint pain, or pain/redness/swelling at the injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (such as anxiety, nervousness, confusion, agitation), signs of infection (such as fever, chills), numb/tingling/pale skin, fast/slow/irregular heartbeat, vision changes, chest pain, unusual bruising/bleeding.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Flolan (epoprostenol sodium) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using epoprostenol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart failure (on the left side of the heart), bleeding problems (such as bleeding of the stomach/intestines), blood disorders (such as thrombocytopenia), liver disease.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

To lower your risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is unknown if this drug passes into breast milk. Discuss the risks and benefits with your doctor before breast-feeding.

Disclaimer

Flolan Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: antiplatelet drugs (such as clopidogrel).

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (aspirin, NSAIDs such as ibuprofen, naproxen) that can increase the risk of bleeding or medicines (such as cough-and-cold products, diet aids) that could increase your blood pressure or heart rate. Ask your pharmacist about using those products safely.

However, if your doctor has directed you to take low-dose aspirin for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day), you should continue taking it unless your doctor instructs you otherwise. Ask your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe dizziness.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as blood pressure, heart rate) should be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: This drug is to be given continuously as an infusion. If your infusion is interrupted, contact your doctor or pharmacist immediately.

STORAGE: Store unopened vials at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Consult your pharmacist for details about the storage of opened vials and prepared solutions. Do not freeze. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised May 2011. Copyright(c) 2011 First Databank, Inc.

Flolan Patient Information Including Side Effects

Brand Names: Flolan, Veletri

Generic Name: epoprostenol (Pronunciation: EE poe PROST en ol)

What is epoprostenol (Flolan)?

Epoprostenol is a prostaglandin (a hormone-like substance that occurs naturally in the body). Prostaglandins help to control functions in the body such as blood pressure and muscle contractions.

Epoprostenol is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise.

Epoprostenol may also be used for purposes not listed in this medication guide.

What are the possible side effects of epoprostenol (Flolan)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • fever, flu symptoms, mouth and throat ulcers, rapid heart rate, rapid and shallow breathing, fainting;
  • chest pain, trouble breathing;
  • fast, slow, or uneven heart rate;
  • pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;
  • blood in your urine or stools;
  • coughing up blood;
  • feeling like you might pass out; or
  • numbness or increased sensitivity anywhere in your body.

Less serious side effects may include:

  • flushing (warmth, redness, or tingly feeling);
  • nausea, vomiting, diarrhea, stomach pain;
  • headache or jaw pain;
  • joint or muscle pain;
  • dizziness, sweating; or
  • feeling anxious, nervous, or agitated.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Flolan (epoprostenol sodium) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about epoprostenol (Flolan)?

You should not use this medication if you are allergic to epoprostenol, if you have breathing problems when you first start using epoprostenol, or if you have congestive heart failure caused by a decrease in your heart's ability to pump blood back into the body.

Before using epoprostenol, tell your doctor if you have a bleeding or blood clotting disorder, heart disease, liver or kidney disease, or high blood pressure.

Epoprostenol is injected into a vein using an infusion pump, usually through a permanent central intravenous (IV) catheter placed into a large vein (such as in your chest). You may need to use this medication for many years.

You may be shown how to use an infusion pump at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

You will receive your first dose of this medicine in a hospital or clinic setting to quickly treat any serious side effects that occur. Your blood pressure and heart rate may also need to be monitored whenever your dose is changed.

Tell your doctor about all other drugs you use, especially medicines to prevent blood clots.

Do not stop using epoprostenol without first talking to your doctor, even if you feel fine or have no symptoms. Even short breaks in the flow of your medication through the IV can cause the treatment to stop working. Missing doses or stopping suddenly may make your condition worse and you may have symptoms such as dizziness, weakness, or trouble breathing.

Call your doctor if your symptoms do not improve, or if they get worse while using epoprostenol.

Side Effects Centers

Flolan Patient Information including How Should I Take

What should I discuss with my healthcare provider before using epoprostenol (Flolan)?

You should not use this medication if you are allergic to epoprostenol, if you have breathing problems when you first start using epoprostenol, or if you have congestive heart failure caused by a decrease in your heart's ability to pump blood back into the body.

To make sure you can safely use epoprostenol, tell your doctor if you have any of these other conditions:

  • a bleeding or blood clotting disorder;
  • heart disease;
  • high blood pressure;
  • kidney disease; or
  • liver disease.

FDA pregnancy category B. Epoprostenol is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether epoprostenol passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use epoprostenol (Flolan)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. You may need to use this medication for many years.

Epoprostenol is injected into a vein using a computerized, portable infusion pump to control the rate of medication you receive. Because epoprostenol must be used long-term, it is usually given through a permanent central intravenous (IV) catheter placed into a large vein (such as in your chest).

You may be shown how to use an infusion pump at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

You will receive your first dose of this medicine in a hospital or clinic setting to quickly treat any serious side effects that occur. Your blood pressure and heart rate may also need to be monitored whenever your dose is changed.

You may be given other medications to prevent blood clots while you are receiving epoprostenol.

Epoprostenol is a powder medicine that must be mixed with a liquid (diluent) before using it. Use only the diluent provided with your medication and do not mix epoprostenol with any other medications or diluents not approved by your doctor.

If you are using the injections at home, be sure you understand how to properly mix and store the medicine. These directions are different for the Flolan and Veletri brands of this medication. Be sure you understand all mixing and storage directions for the specific brand of epoprostenol you are using.

After mixing Flolan with the diluent, store in the refrigerator and use within 48 hours. After mixing Veletri with the diluent, store in the refrigerator ans use within 5 days.

The Veletri and diluent mixture may also be stored at room temperature but you must use it within 48 hours after it was mixed.

Protect the mixed medicine from light and do not freeze. Throw away any epoprostenol and diluent mixture that has become frozen, has changed colors, or has any particles in it. Call your doctor for a new prescription. The epoprostenol and diluent mixture must be protected from light at all times, whether it is in storage or in use.

Do not stop using epoprostenol without first talking to your doctor, even if you feel fine or have no symptoms. Missing doses or stopping suddenly may make your condition worse and you may have symptoms such as dizziness, weakness, or trouble breathing.

Even short breaks in the flow of your medication through the IV can cause the treatment to stop working. To make sure there is no interruption in your treatment, you may need to have a back-up infusion pump in case your first pump fails to work properly. Also keep replacement batteries and extra IV infusion sets on hand at all times. Get your prescription refilled before you run out of medicine completely.

Call your doctor if your symptoms do not improve, or if they get worse while using epoprostenol.

Store unopened vials of epoprostenol and its diluent at cool room temperature (below 77 degrees F), away from moisture, heat, and light. Keep in the original carton.

Side Effects Centers

Flolan Patient Information including If I Miss a Dose

What happens if I miss a dose (Flolan)?

Because this medication is given around the clock, you should not miss a dose if you use the medication properly. Call your doctor right away if your epoprostenol therapy is interrupted for any reason.

What happens if I overdose (Flolan)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

What should I avoid while using epoprostenol (Flolan)?

Avoid using any infusion pump that has not been approved for use by your doctor.

What other drugs will affect epoprostenol (Flolan)?

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 (non-steroidal 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.

Where can I get more information?

Your doctor or pharmacist can provide more information about epoprostenol.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.01. Revision date: 5/31/2011.

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