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| Product NDC Code | 0173-0857 | ||||
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| Drug Name | Diluent |
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| Type | Brand | ||||
| Active Ingredients |
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| Route | INTRAVENOUS | ||||
| Dosage Form | SOLUTION | ||||
| RxCUI drug identifier | 211199, 211200, 562501, 562502 |
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| Application Number | NDA020444 | ||||
| Labeler Name | GlaxoSmithKline LLC | ||||
| Packages |
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Overdosage of Diluent
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The most common adverse reactions are dizziness, jaw pain, headache, musculoskeletal pain, and nausea/vomiting, and are generally associated with vasodilation. ( 6 ) 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 2 and are generally related to vasodilatory effects. Table 2. Adverse Reactions Occurring in Patients with Idiopathic or Heritable PAH and with PAH Associated with Scleroderma Spectrum of Diseases (PAH/SSD) Occurring ≥10% More Frequently on FLOLAN than Conventional Therapy 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% PAH = Pulmonary Arterial Hypertension, SSD = Scleroderma Spectrum of Diseases. 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. Cardiac High output cardiac failure. Endocrine and Metabolic Hyperthyroidism. Gastrointestinal Hepatic failure. Respiratory, Thoracic, and Mediastinal Pulmonary embolism.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Epoprostenol has 2 major pharmacological actions: (1) 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 humans, 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 Interaction Studies 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-PGF 1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF 1α (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 Interaction Studies 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.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds and (2) inhibition of platelet aggregation.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.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 humans, 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 Interaction Studies 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.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-PGF 1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF 1α (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 Interaction Studies 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.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS FLOLAN is contraindicated in patients with heart failure caused by reduced left ventricular ejection fraction [see Clinical Studies ( 14.3 )] . FLOLAN is contraindicated in patients with a hypersensitivity to the drug or any of its ingredients. • Heart failure with reduced ejection fraction. ( 4 ) • Hypersensitivity to FLOLAN or any of its ingredients. ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.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 epoprostenol sodium 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 (PGI 2 , 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,13 E ,15 S )-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 C 20 H 31 NaO 5 . The structural formula is: FLOLAN must be reconstituted with pH 12 STERILE DILUENT for FLOLAN. 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 the pH to 11.7 to 12.3), and Water for Injection. The stability of reconstituted solutions of FLOLAN is pH-dependent and is greater at higher pH. epoprostenol sodium chemical structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION • Initiate intravenous infusion through a central venous catheter at 2 ng/kg/min. ( 2.2 , 2.3 ) • Change dose in 1- to 2-ng/kg/min increments at intervals of at least 15 minutes based on clinical response. ( 2.2 ) • Avoid sudden large dose reductions. ( 2.2 , 5.2 ) 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 [see Dosage and Administration ( 2.3 )] . Using aseptic technique, reconstitute FLOLAN only with pH 12 STERILE DILUENT for FLOLAN. Table 1 gives directions for preparing several different concentrations of FLOLAN. See storage and administration time limits for the reconstituted FLOLAN below. Table 1. Reconstitution and Dilution Instructions for FLOLAN Using pH 12 STERILE DILUENT for FLOLAN. a Higher concentrations may be prepared for patients who receive FLOLAN long-term. 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/mL a 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. Storage and Administration Limits for Reconstituted FLOLAN • 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: • 48 hours at up to 25°C (77°F). • 36 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). Discard any unused solution after these times. • 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 [see Adverse Reactions ( 6.1 , 6.2 )] . Avoid abrupt withdrawal of FLOLAN or sudden large reductions in infusion rates [see Warnings and Precautions ( 5.2 )] . 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. Preparation and administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG) may become damaged when used with FLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN and therefore must not be used. Consult the manufacturer of the sets to confirm that they are considered compatible with highly alkaline solutions, such as FLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN. 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 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
| a Higher concentrations may be prepared for patients who receive FLOLAN long-term. | |
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.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 of epoprostenol freeze-dried powder in a single-dose vial for reconstitution with the supplied diluent. ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.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 )
Spl product data elements
Usually a list of ingredients in a drug product.FLOLAN epoprostenol sodium EPOPROSTENOL SODIUM EPOPROSTENOL GLYCINE SODIUM CHLORIDE MANNITOL FLOLAN epoprostenol sodium EPOPROSTENOL SODIUM EPOPROSTENOL GLYCINE SODIUM CHLORIDE MANNITOL Diluent water WATER WATER GLYCINE SODIUM CHLORIDE SODIUM HYDROXIDE
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.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. In a fertility/postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at an adult toxic dose of up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the MRHD based on body surface area). There was no effect on fertility in female or male rats.
Nonclinical toxicology
Information about toxicology in non-human subjects.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. In a fertility/postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at an adult toxic dose of up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the MRHD based on body surface area). There was no effect on fertility in female or male rats.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL NDC 0173-0517-00 FLOLAN (epoprostenol sodium) for Injection 0.5 mg/vial (500,000 ng/vial) Must be reconstituted. For intravenous infusion after dilution. Note: Use only pH 12 STERILE DILUENT for FLOLAN for reconstitution and dilution. R x only Single-Use Vial Each vial contains epoprostenol sodium equivalent to 0.5 mg (500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH. Usual Dose: See prescribing information. Store at 15 o and 25 o C (59 o to 77 o F). Protect from light. Do not accept if plastic overseal is missing or not securely fitted. GlaxoSmithKline RTP, NC 27709 Rev. 3/22 62000000077639 Flolan 0.5 mg label
PRINCIPAL DISPLAY PANEL NDC 0173-0519-00 FLOLAN (epoprostenol sodium) for Injection 1.5 mg/vial (1,500,000 ng/vial) Must be reconstituted. For intravenous infusion after dilution. Note: Use only pH 12 STERILE DILUENT for FLOLAN for reconstitution and dilution. R x only Single-Use Vial Each vial contains epoprostenol sodium equivalent to 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH. Usual Dose: See prescribing information. Store at 15 o and 25 o C (59 o to 77 o F). Protect from light. Do not accept if plastic overseal is missing or not securely fitted. GlaxoSmithKline RTP, NC 27709 Rev. 3/22 62000000077633 Flolan 1.5 mg label
PRINCIPAL DISPLAY PANEL NDC 0173-0857-02 pH 12 Sterile Diluent for FLOLAN Rx only Use only with FLOLAN (epoprostenol sodium) for Injection Single-Dose Vial. Discard Unused Portion. 2 vials, each vial contains 50 mL GSK Made in England ©2023 GSK group of companies or its licensor. Rev. 09/23 62000000090121 Flolan Diluent pH 12 carton
Diluent: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Advise patients: • FLOLAN must be reconstituted only with pH 12 STERILE DILUENT for FLOLAN. • Reconstituted solutions prepared with pH 12 STERILE DILUENT for FLOLAN do NOT require use with a cold pouch. • FLOLAN is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with FLOLAN 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 may result in rapid symptomatic deterioration. A patient’s decision to receive FLOLAN should be based upon the understanding that there is a high likelihood that therapy with FLOLAN will be needed for prolonged periods, possibly years. Consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump. • FLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing PET or PETG. Only use materials provided by a healthcare provider or pharmacist. • To adjust infusion rates of FLOLAN only under the direction of a physician. • To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. • To contact their healthcare providers if any unusual bruising or bleeding develops. Trademark is owned by or licensed to the GSK group of companies. GlaxoSmithKline Durham, NC 27701 ©2023 GSK group of companies or its licensor. FLL:11PI
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.PATIENT INFORMATION FLOLAN (flow-lan) (epoprostenol sodium) for injection, for intravenous use 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. Do not use FLOLAN if you : • have certain types of heart failure. Talk to your healthcare provider before using FLOLAN if you have heart failure. • are allergic to FLOLAN or any of the ingredients in FLOLAN. See the end of this leaflet for a complete list of ingredients in FLOLAN. Before you use FLOLAN, tell your healthcare provider about all of your medical conditions, including if you: • are allergic to any medicine. • are pregnant or plan to become pregnant. It is not known if FLOLAN will harm your unborn baby. You and your healthcare provider should decide if you will use FLOLAN. • are breastfeeding or plan to breastfeed. It is not known if FLOLAN passes into your breast milk. You and your healthcare provider should decide if you will take FLOLAN or breastfeed. You should not do both. 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: • a “water pill” (diuretic) • a medicine for high blood pressure (hypertension) • a blood thinner medicine (antiplatelet or anticoagulant medicine) 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 your medicines with you to show your healthcare provider and pharmacist when you get a new medicine. How should I use FLOLAN? • FLOLAN should only be given by infusion through a catheter placed in a vein (intravenous infusion) using an infusion pump. • Your first treatment will be given to you by your healthcare provider or nurse. This is so your healthcare provider can monitor you and find the best dose for you. • If your healthcare provider decides that you or your caregiver can give infusions of FLOLAN at home, you or your caregiver will receive training on the right way to mix and infuse FLOLAN. Do not try to infuse FLOLAN until you have been shown the right way to infuse FLOLAN by your healthcare provider. • Treatment will be needed for a long period of time, possibly years. You must be able to accept and care for a catheter and infusion pump in order to be treated with FLOLAN. • Use FLOLAN exactly as your healthcare provider tells you to. • Do not change your dose or stop your infusion without talking to your healthcare provider. Stopping FLOLAN suddenly can cause serious side effects. • You should have a backup infusion pump and extra supplies needed for your infusion of FLOLAN. • Follow your healthcare provider’s instructions for taking blood thinner medicines, if prescribed for you. • Before you use FLOLAN, you must mix (reconstitute) FLOLAN powder with pH 12 STERILE DILUENT for FLOLAN (comes in a plastic bottle) . • Do not mix FLOLAN with any other diluent. You must use pH 12 STERILE DILUENT for FLOLAN. • FLOLAN prepared with pH 12 STERILE DILUENT for FLOLAN must not be used with any preparation or administration materials containing polyethylene terephthalate (PET) or polyethylene terephthalate glycol (PETG). Only use materials provided by a healthcare provider or pharmacist. See “ How should I store and use FLOLAN? ” for more information about how to use and store FLOLAN the right way. • A mixed solution of FLOLAN is clear and colorless. Do not use FLOLAN if the mixed solution looks discolored or cloudy, or if the solution has flakes or particles in it. 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: • Fluid in your lungs (pulmonary edema) . If you develop pulmonary edema after starting FLOLAN, your healthcare provider will stop your treatment and you should not receive FLOLAN again. • Worsening symptoms of pulmonary arterial hypertension (PAH) with a sudden decrease in the dose of FLOLAN . Do not change your dose of FLOLAN or stop your infusion without talking to your healthcare provider. If you suddenly stop or decrease your dose of FLOLAN you may develop worsening symptoms of your PAH, including shortness of breath, dizziness, weakness, or loss of strength. • Widening of your blood vessels (vasodilation) . Vasodilation reactions can happen after you start FLOLAN. These reactions are common and may cause low blood pressure (hypotension), flushing, nausea, vomiting, dizziness, and headache. Your healthcare provider should check your blood pressure regularly during treatment with FLOLAN, especially when you start FLOLAN and after your dose is changed. • Increased risk for bleeding . FLOLAN affects how well your blood clots, so your risk for bleeding is increased. This is especially true if you have other risk factors for bleeding. Tell your healthcare provider if you develop any unusual bruising or bleeding. The most common side effects of FLOLAN include: • dizziness • jaw pain • headache • muscle or bone pain • nausea or vomiting 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? • Store FLOLAN powder at room temperature between 59°F to 77°F (15°C to 25°C). • Protect FLOLAN powder from light. Keep unopened vial of FLOLAN in the carton until you are ready to mix. • Store the pH 12 STERILE DILUENT for FLOLAN at room temperature, 59°F to 77°F (15°C to 25°C). Do not freeze. • Vials of pH 12 STERILE DILUENT for FLOLAN are for one-time use only. Throw away any unused diluent. • Throw away any vials of FLOLAN powder and pH 12 STERILE DILUENT for FLOLAN that are out of date or that you no longer need. How to store mixed solutions of FLOLAN: • Once FLOLAN and the diluent are mixed together, you may use right away or store in the refrigerator. Refrigerate at 36°F to 46°F (2°C to 8°C). • Protect the mixed solution of FLOLAN from light until you are ready to use it. • Do not freeze mixed solutions. Throw away any mixed solution that has been frozen. • Freshly prepared mixed solutions may be stored in the refrigerator for up to 8 days . Mixed solutions (freshly prepared or taken out of the refrigerator) are stable for up to 48 hours at 77°F (25°C), up to 36 hours at 86°F (30°C), up to 24 hours at 95°F (35°C) or up to 12 hours at 104°F (40°C). Discard any unused solution after these times. • FLOLAN mixed with pH 12 STERILE DILUENT for FLOLAN does not require use with a cold pouch. • Throw away any mixed solution if it has been refrigerated for more than 8 days . 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 that you have. It may harm them. This leaflet summarizes the most important information about FLOLAN. You can ask your healthcare provider or pharmacist for information about FLOLAN that is written for health professionals. What are the ingredients in FLOLAN? Active ingredient: epoprostenol sodium. Inactive ingredients: glycine, mannitol, sodium chloride. Sodium hydroxide may have been added. The pH 12 STERILE DILUENT for FLOLAN contains: glycine, sodium chloride, sodium hydroxide, and Water for Injection. GlaxoSmithKline Durham, NC 27701 Trademark is owned by or licensed to the GSK group of companies. ©2023 GSK group of companies or its licensor. FLL:7PIL This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 10/2023
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.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 ( 2 ) 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 3 illustrates the treatment‑related hemodynamic changes in these patients after 8 or 12 weeks of treatment. Table 3. Hemodynamics during Chronic Administration of FLOLAN in Patients with Idiopathic or Heritable PAH CI = Cardiac index, PAPm = Mean pulmonary arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure, SV = Stroke volume, TPR = Total pulmonary resistance. a At 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). b Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy. Baseline Mean Change from Baseline at End of Treatment Period a Hemodynamic Parameter FLOLAN (n = 52) Standard Therapy (n = 54) FLOLAN (n = 48) Standard Therapy (n = 41) CI (L/min/m 2 ) 2.0 2.0 0.3 b -0.1 PAPm (mm Hg) 60 60 -5 b 1 PVR (Wood U) 16 17 -4 b 1 SAPm (mm Hg) 89 91 -4 -3 SV (mL/beat) 44 43 6 b -1 TPR (Wood U) 20 21 -5 b 1 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 4 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment. Table 4. Hemodynamics during Chronic Administration of FLOLAN in Patients with PAH/SSD CI = Cardiac index, PAPm = Mean pulmonary arterial pressure, RAPm = Mean right arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure. a Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy (n is the number of patients with hemodynamic data). 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/m 2 ) 1.9 2.2 0.5 a -0.1 PAPm (mm Hg) 51 49 -5 a 1 RAPm (mm Hg) 13 11 -1 a 1 PVR (Wood U) 14 11 -5 a 1 SAPm (mm Hg) 93 89 -8 a -1 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.
| CI = Cardiac index, PAPm = Mean pulmonary arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure, SV = Stroke volume, TPR = Total pulmonary resistance. | ||||
| a At 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). b Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy. | ||||
| CI = Cardiac index, PAPm = Mean pulmonary arterial pressure, RAPm = Mean right arterial pressure, PVR = Pulmonary vascular resistance, SAPm = Mean systemic arterial pressure. | ||||
| a Denotes statistically significant difference between group receiving FLOLAN and group receiving conventional therapy (n is the number of patients with hemodynamic data). | ||||
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.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.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary Limited published data from case series and case reports have not established an association with FLOLAN and major birth defects, miscarriage or adverse maternal or fetal outcomes when FLOLAN is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations) . In animal reproduction studies, pregnant rats and rabbits received epoprostenol sodium during organogenesis at exposures of 2.5 and 4.8 times the maximum recommended human dose (MRHD), respectively, and there was no effect on the fetus (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data: Embryo-fetal development studies have been performed in rats and rabbits during organogenesis. Epoprostenol sodium doses up to 100 mcg/kg/day, a dose that was maternally toxic in rabbits but not in rats (600 mcg/m 2 /day in rats, 2.5 times the MRHD, and 1,180 mcg/m 2 /day in rabbits, 4.8 times the MRHD based on body surface area), had no effect on the fetus. In a postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at a male and female toxic dose of up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the MRHD based on body surface area). There was no effect on growth and development of the offspring.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from case series and case reports have not established an association with FLOLAN and major birth defects, miscarriage or adverse maternal or fetal outcomes when FLOLAN is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations) . In animal reproduction studies, pregnant rats and rabbits received epoprostenol sodium during organogenesis at exposures of 2.5 and 4.8 times the maximum recommended human dose (MRHD), respectively, and there was no effect on the fetus (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data: Embryo-fetal development studies have been performed in rats and rabbits during organogenesis. Epoprostenol sodium doses up to 100 mcg/kg/day, a dose that was maternally toxic in rabbits but not in rats (600 mcg/m 2 /day in rats, 2.5 times the MRHD, and 1,180 mcg/m 2 /day in rabbits, 4.8 times the MRHD based on body surface area), had no effect on the fetus. In a postnatal development study, epoprostenol sodium was administered subcutaneously to female rats for 2 weeks prior to mating through weaning and to male rats for 60 days prior to and through mating at a male and female toxic dose of up to 100 mcg/kg/day (600 mcg/m 2 /day, 2.5 times the MRHD based on body surface area). There was no effect on growth and development of the offspring. 8.2 Lactation Risk Summary There are no data on the presence of epoprostenol in either human or animal milk, the effects on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLOLAN and any potential adverse effects on the breastfed child from epoprostenol or from the underlying maternal condition. 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.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.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. 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 (500,000 ng) 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 pH 12 STERILE DILUENT for FLOLAN 50 mL per vial (NDC 0173-0857-01), 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 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.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API