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Flolan

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Flolan uses


1 INDICATIONS AND USAGE

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

Flolan is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly (97%) patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (49%) or PAH associated with connective tissue diseases (51%). (1)

2 DOSAGE AND ADMINISTRATION

2.1 Reconstitution

Each vial is for single use only; discard any unused diluent or unused reconstituted solution.

Select a concentration for the solution of Flolan 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 below .

Using aseptic technique, reconstitute Flolan only with STERILE DILUENT for Flolan or pH 12 STERILE DILUENT for Flolan. Table 1 gives directions for preparing several different concentrations of Flolan. See Table 2 for storage and administration time limits for the reconstituted Flolan.


To make 100 mL of solution with final concentration of:


Directions:


3,000 ng/mL

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.

5,000 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.

10,000 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.

15,000 ng/mLa


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.

When Using

STERILE DILUENT

for Flolan


When Using

pH 12 STERILE DILUENT

for Flolan


Stability


When used at room temperature, (15°C to 25°C; 59°F to 77°F) reconstituted solutions:

  • are stable for up to 8 hours following reconstitution or removal from refrigerated storage.
  • may be stored for up to 40 hours refrigerated at 2°C to 8°C (36°F to 46°F) before use.

When used with a cold pack, reconstituted solutions:

  • are stable for up to 24 hours use.
  • may be stored refrigerated at 2°C to 8°C (36°F to 46°F) before use as long as the total time of refrigerated storage and infusion does not exceed 48 hours.
  • Change cold packs every 12 hours.

Freshly prepared reconstituted solutions or reconstituted solutions that have been stored at 2°C to 8°C (36°F to 46°F) for no longer than 8 days can be administered up to:

  • 72 hours at up to 25°C (77°F).
  • 48 hours at up to 30°C (86°F).
  • 24 hours at up to 35°C (95°F).
  • 12 hours at up to 40°C (104°F).
  • Reconstituted solutions can be used immediately. Refrigerate at 2°C to 8°C (36°F to 46°F) if not used immediately.
  • Protect from light.
  • Do not freeze reconstituted solutions.

2.2 Dosage

Initiate intravenous infusions of Flolan at 2 ng/kg/min. Alter 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.

During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output may occur. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

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 vasodilatory reactions. In general, expect progressive increases in dose.

If dose-related adverse reactions occur, make dose decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve . Avoid abrupt withdrawal of Flolan or sudden large reductions in infusion rates .

Following establishment of a new chronic infusion rate, measure standing and supine blood pressure for several hours.

Taper doses of Flolan after initiation of cardiopulmonary bypass in patients receiving lung transplants.

2.3 Administration

Initiate Flolan in a setting with adequate personnel and equipment for physiologic monitoring and emergency care.

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Administer continuous chronic infusion of Flolan through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Do not administer bolus injections of Flolan.

The ambulatory infusion pump used to administer Flolan 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. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. Use a 60-inch microbore non-di-(2-ethylhexyl)phthalate (DEHP) extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22-micron filter.

To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets.

Do not administer or dilute reconstituted solutions of Flolan with other parenteral solutions or medications. Consider a multi‑lumen catheter if other intravenous therapies are routinely administered.

Select a concentration for the solution of Flolan 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 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 or 2 vials of pH 12 STERILE DILUENT for Flolan.

Generally, 3,000 ng/mL and 10,000 ng/mL are satisfactory concentrations to deliver between 2 to 16 ng/kg/min in adults. Higher infusion rates, and therefore, more concentrated solutions may be necessary with long‑term administration of Flolan.

Infusion rates may be calculated using the following formula:

Flolan infusion rate formula

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3 DOSAGE FORMS AND STRENGTHS

For injection: 0.5 mg or 1.5 mg of epoprostenol, freeze-dried powder in a single-dose vial for reconstitution with the supplied diluent.

For injection: 0.5 mg or 1.5 mg epoprostenol freeze-dried powder in a single use vial for reconstitution with the supplied diluent. (3)

4 CONTRAINDICATIONS

Flolan is contraindicated in patients with heart failure caused by reduced left ventricular ejection fraction .

Flolan is contraindicated in patients with a hypersensitivity to the drug or any of its ingredients.

5 WARNINGS AND PRECAUTIONS

5.1 Pulmonary Edema

If the patient develops pulmonary edema during initiation with Flolan, discontinue therapy and do not readminister. Consider the possibility of associated pulmonary veno-occlusive disease in such patients.

5.2 Rebound Pulmonary Hypertension following Abrupt Withdrawal

Avoid abrupt withdrawal or sudden large reductions in dosage of Flolan because symptoms associated with rebound pulmonary hypertension (e.g., dyspnea, dizziness, and asthenia) may occur. In clinical trials, one Class III patient's death was judged attributable to the interruption of Flolan.

5.3 Vasodilation

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

5.4 Increased Risk for Bleeding

Flolan is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding .

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6 ADVERSE REACTIONS

The most common adverse reactions are dizziness, jaw pain, headache, musculoskeletal pain, and nausea/vomiting, and are generally associated with vasodilation.

To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions are shown in Table 3 and are generally related to vasodilatory effects.


Adverse Reaction


Idiopathic or Heritable

PAH


PAH/SSD


Flolan


Conventional Therapy


Flolan


Conventional Therapy


(n = 52)


(n = 54)


(n = 56)


(n = 55)


Body as a whole


Jaw pain

54%

0%

75%

0%

Nonspecific musculoskeletal pain

35%

15%

84%

65%

Headache

83%

33%

46%

5%

Chills/fever/sepsis/flu-like symptoms

25%

11%

13%

11%

Cardiovascular system


Flushing

42%

2%

23%

0%

Hypotension

27%

31%

13%

0%

Tachycardia

35%

24%

43%

42%

Digestive system


Anorexia

25%

30%

66%

47%

Nausea/Vomiting

67%

48%

41%

16%

Diarrhea

37%

6%

50%

5%

Skin and Appendages


Skin ulcer

-

-

39%

24%

Eczema/rash/urticaria

10%

13%

25%

4%

Musculoskeletal System


Myalgia

44%

31%

-

-

Nervous system


Anxiety/hyperkinesias/nervousness/tremor

21%

9%

7%

5%

Hyperesthesia/hypesthesia/paresthesia

12%

2%

5%

0%

Dizziness

83%

70%

59%

76%

Adverse Events Attributable to the Drug Delivery System

Chronic infusions of Flolan 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.

6.2 Postmarketing Experience

The following events have been identified during postapproval use of Flolan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic

Anemia, hypersplenism, pancytopenia, splenomegaly, thrombocytopenia.

Endocrine and Metabolic

Hyperthyroidism.

Gastrointestinal

Hepatic failure.

Respiratory, Thoracic, and Mediastinal

Pulmonary embolism.

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8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Flolan should be used during pregnancy only if clearly needed.

Animal Data

Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100 mcg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to Flolan.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Flolan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials of Flolan in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

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10 OVERDOSAGE

Signs and Symptoms

Hypoxemia, hypotension, and respiratory arrest leading to death have been reported in clinical practice following overdosage of Flolan.

Excessive doses of Flolan were associated with flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea during clinical trials.

One patient with PAH/SSD accidentally received 50 mL of an unspecified concentration of Flolan. The patient vomited and became unconscious with an initially unrecordable blood pressure. Flolan was discontinued and the patient regained consciousness within seconds.

Single intravenous doses of Flolan 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.

Treatment

Discontinue or reduce dose of Flolan.

11 DESCRIPTION

Flolan (epoprostenol sodium) for injection is sterile sodium salt that is a white or off-white powder formulated for intravenous (IV) administration. Each vial of Flolan contains Flolan equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 50 mg mannitol, and 2.93 mg sodium chloride. 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. The chemical name of epoprostenol is (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid. Flolan has a molecular weight of 374.45 and a molecular formula of C20H31NaO5. The structural formula is:

Flolan must be reconstituted with either STERILE DILUENT for Flolan or pH 12 STERILE DILUENT for Flolan.

STERILE DILUENT for Flolan is supplied in glass vials and pH 12 STERILE DILUENT for Flolan is supplied in plastic vials each containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection. The stability of reconstituted solutions of Flolan is pH-dependent, and is greater at higher pH.

Flolan chemical structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Acute Hemodynamic Effects

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

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

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

Drug Interactions

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

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

12.3 Pharmacokinetics

Absorption/Distribution

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

Metabolism

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

Elimination

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

Drug Interactions

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

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

13 NONCLINICAL TOXICOLOGY

13.1 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 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).

14 CLINICAL STUDIES

14.1 Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects

Chronic continuous infusions of Flolan in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing Flolan plus conventional therapy with conventional therapy alone. Dosage of Flolan was determined as described in Dosage and Administration and averaged 9.2 ng/kg/min at trials’ 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 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 trials, 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 chronically compared with those who did not. Table 4 illustrates the treatment‑related hemodynamic changes in these patients after 8 or 12 weeks of treatment.


Baseline


Mean Change from Baseline at End of Treatment Perioda


Hemodynamic

Parameter


Flolan

(n = 52)


Standard Therapy

(n = 54)


Flolan

(n = 48)


Standard Therapy

(n = 41)


CI

(L/min/m2)

2.0

2.0

0.3b


-0.1

PAPm

(mm Hg)

60

60

-5b


1

PVR

(Wood U)

16

17

-4b


1

SAPm

(mm Hg)

89

91

-4

-3

SV

(mL/beat)

44

43

6b


-1

TPR

(Wood U)

20

21

-5b


1

aAt 8 weeks: Flolan n = 10, conventional therapy n = 11 (n is the number of patients with hemodynamic data).

At 12 weeks: Flolan n = 38, conventional therapy n = 30 (n is the number of patients with hemodynamic data).

bDenotes statistically significant difference between group receiving Flolan and group receiving conventional therapy.

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 was administered for at least 36 months in an open, nonrandomized trial.

The acute hemodynamic response to Flolan did not correlate well with improvement in exercise tolerance or survival during chronic use of Flolan.

Clinical Effects

A statistically significant improvement was observed in exercise capacity, as measured by the 6‑minute walk test in patients receiving continuous intravenous Flolan plus conventional therapy (n = 52) for 8 or 12 weeks compared with 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, respectively.

Survival was improved in NYHA Functional Class III and Class IV patients with idiopathic or heritable PAH treated with Flolan for 12 weeks in a multicenter, open, randomized, parallel trial. 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 died (P = 0.003).

14.2 Chronic Infusion in PAH/SSD

Hemodynamic Effects

Chronic continuous infusions of Flolan in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing Flolan plus conventional therapy (n = 56) with conventional therapy alone (n = 55). Except for 5 NYHA Functional Class II patients, all patients were either functional Class III or Class IV. 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.

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 chronically compared with those who did not. Table 5 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.


Baseline


Mean Change from Baseline at 12 Weeks


Hemodynamic

Parameter


Flolan

(n = 56)


Conventional Therapy

(n = 55)


Flolan

(n = 50)


Conventional Therapy

(n = 48)


CI

(L/min/m2)

1.9

2.2

0.5a


-0.1

PAPm

(mm Hg)

51

49

-5a


1

RAPm

(mm Hg)

13

11

-1a


1

PVR

(Wood U)

14

11

-5a


1

SAPm

(mm Hg)

93

89

-8a


-1

aDenotes statistically significant difference between group receiving Flolan and group receiving conventional therapy (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 plus conventional therapy for 12 weeks compared with 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 compared with none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with Flolan and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with Flolan and 13/48 (27%) with conventional therapy alone worsened.

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

14.3 Increased Mortality in Patients with Heart Failure Caused by Severe Left Ventricular Systolic Dysfunction

A large trial evaluating the effect of Flolan 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 plus conventional therapy than in those receiving conventional therapy alone. The chronic use of Flolan in patients with heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Flolan for injection is supplied as a sterile freeze‑dried powder in 17‑mL flint glass vials with gray butyl rubber closures.

STERILE DILUENT for Flolan is supplied in flint glass vials containing 50‑mL diluent with fluororesin‑faced butyl rubber closures with aluminum overseal and yellow plastic flip-off cap.

pH 12 STERILE DILUENT for Flolan is supplied in plastic vials containing 50‑mL diluent with fluororesin‑faced butyl rubber closures with aluminum overseal and lavender plastic flip-off cap.


Flolan for injection

0.5-mg per vial, carton of 1

NDC 0173-0517-00

1.5-mg (1,500,000 ng) per vial, carton of 1

NDC 0173-0519-00

STERILE DILUENT

for Flolan


50 mL per vial, carton of 2

NDC 0173-0518-01

pH 12 STERILE DILUENT for Flolan

50 mL per vial, carton of 2

NDC 0173-0857-02

16.2 Storage and Handling

Proper storage and handling are essential to maintain the potency of Flolan for injection.

Unopened vials of Flolan powder are stable until the date indicated on the package when stored at room temperature, 15°C to 25°C (59°F to 77°F) and protected from light in the carton.

Unopened vials of STERILE DILUENT for Flolan and pH 12 STERILE DILUENT for Flolan are stable until the date indicated on the package when stored at room temperature, 15°C to 25°C (59°F to 77°F). DO NOT FREEZE.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advise patients:


Flolan is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2016 the GSK group of companies. All rights reserved.

FLL:5PI

PHARMACIST‑DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

_ _ __ _ __ _ __ _ __ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _

PATIENT INFORMATION

Flolan® (flow-lan)

(epoprostenol sodium)

for injection

Read this Patient Information before you start taking Flolan and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is Flolan?

Flolan is a prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of the lungs. Flolan can improve your ability to be physically active.

It is not known if Flolan is safe and effective in children.

Who should not use Flolan?

Do not use Flolan if you:


What should I tell my healthcare provider before using Flolan?

Before you use Flolan, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take:


Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.

How should I use Flolan?


Using more than the prescribed dose of Flolan can lead to death. If you use more than the prescribed dose of Flolan, call your healthcare provider or go to the nearest emergency room right away.

What are the possible side effects of Flolan?

Flolan can cause serious side effects, including:


The most common side effects of Flolan include:


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Flolan. For more information, ask your healthcare provider or pharmacist.

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

How should I store and use Flolan?


How to store mixed solutions of Flolan:


Keep Flolan and all medicines out of the reach of children.

General information about the safe and effective use of Flolan

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Flolan for a condition for which it was not prescribed. Do not give Flolan to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Flolan. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Flolan that is written for health professionals.

For more information, go to www. FLOLAN.com or call 1-888-825-5249.

What are the ingredients in Flolan?

Active ingredient: Flolan.

Inactive ingredients: glycine, mannitol, sodium chloride. Sodium hydroxide may have been added.

The STERILE DILUENT for Flolan and the pH 12 STERILE DILUENT for Flolan contain: glycine, sodium chloride, sodium hydroxide, and Water for Injection.

This Patient Information has been approved by the U.S. Food and Drug Administration.

GlaxoSmithKline

Research Triangle Park, NC 27709

Flolan is a registered trademark of the GSK group of companies.

©2016 the GSK group of companies. All rights reserved.

Revised: June/2016

FLL:2PIL

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PRINCIPAL DISPLAY PANEL

NDC 0173-0518-00

Flolan pharmaceutical active ingredients containing related brand and generic drugs:


Flolan available forms, composition, doses:


Flolan destination | category:


Flolan Anatomical Therapeutic Chemical codes:


Flolan pharmaceutical companies:


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References

  1. Dailymed."FLOLAN (EPOPROSTENOL SODIUM) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION DILUENT (WATER) SOLUTION [GLAXOSMITHKLINE LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "epoprostenol". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "epoprostenol". http://www.drugbank.ca/drugs/DB0124... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Flolan?

Depending on the reaction of the Flolan after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Flolan not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Flolan addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Flolan, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Flolan consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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