`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These highlights do not include all the information needed to use
`
` FLOLAN safely and effectively. See full prescribing information for
`
`
`
` FLOLAN.
`
`FLOLAN (epoprostenol sodium) for injection, for intravenous use
`
`
`
`Initial U.S. Approval: 1995
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
` Dosage and Administration (2.1 - 2.3)
`
`
`
` 04/2015
`
`
` ----------------------------INDICATIONS AND USAGE ---------------------------­
`
` 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)
`
`
`
`
` ----------------------- 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)
`
`
`
`
`
` --------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` -------------------------------CONTRAINDICATIONS ------------------------------­
` • Heart failure with reduced ejection fraction. (4)
`
`
`
`
`
` • Hypersensitivity to FLOLAN or any of its ingredients. (4)
`
`
`
`
` ----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
` • Pulmonary edema: Discontinue therapy if pulmonary edema occurs. (5.1)
`
`
`
`
`
` • Rebound pulmonary hypertension: Do not abruptly discontinue or decrease
`
`
`
`
`
`
` the dose. (5.2)
` • Vasodilation reactions: Monitor blood pressure and symptoms regularly
`
`
` during initiation and after dose change. (5.3)
`
`
`
` • Increased risk for bleeding: Increased risk for hemorrhagic complications,
`
`
`
`
`
`
`
` particularly for patients with other risk factors for bleeding. (5.4)
`
`
`
`
` ------------------------------ 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.
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`Revised: 04/2015
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Reconstitution
`
`
`2.2 Dosage
`
`
`2.3 Administration
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Pulmonary Edema
`
`5.2 Rebound Pulmonary Hypertension following Abrupt
`
`
`
`Withdrawal
`
`
`5.3 Vasodilation
`
`
`Increased Risk for Bleeding
`5.4
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`
`
`
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Chronic Infusion in Idiopathic or Heritable PAH
`
`
`
`14.2 Chronic Infusion in PAH/SSD
`
`14.3 Increased Mortality in Patients with Heart Failure
`
`
`
`
`Caused by Severe Left Ventricular Systolic Dysfunction
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`16.2 Storage and Handling
`
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`
`
`Reference ID: 3733981
`
`
`
` 1
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1103, p. 1 of 24
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
` 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%).
`
`
`
`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 [see Dosage and Administration (2.4)].
`
`
`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.
`
`
`
`Reference ID: 3733981
`
`
`
` 3
`
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`
`

`

`
`
` Table 1. Reconstitution and Dilution Instructions for FLOLAN Using STERILE DILUENT
`
` for FLOLAN or pH 12 STERILE DILUENT for FLOLAN.
`
`
`To make 100 mL of
`solution with final
`
` concentration of:
`
`
` 3,000 ng/mL
`
`
` 5,000 ng/mL
`
`
`
`
`
`
`
`
`
`
`
`
` Directions:
` 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.
`
`
`
`
` 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.
`
`
`
` Dissolve contents of two 0.5-mg vials each with 5 mL of sterile diluent.
`
`
`
`
`
`
`
` 10,000 ng/mL Withdraw entire vial contents and add sufficient sterile diluent to make a
`
`
` total of 100 mL.
`
` Dissolve contents of one 1.5-mg vial with 5 mL of sterile diluent. Withdraw
`
`
`
` entire vial contents and add sufficient sterile diluent to make a total of
`
`
`
` 100 mL.
` a Higher concentrations may be prepared for patients who receive FLOLAN long-term.
`
`
`
`
`
`15,000 ng/mLa
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3733981
`
`
`
` 4
`
`
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`
`

`

`
`
`
`
`
` Stability
`
`
`
`
`
`
`
`
`Table 2. Storage and Administration Limits for Reconstituted FLOLAN
`
` When Using
`
` When Using
`
` STERILE DILUENT
` pH 12 STERILE DILUENT
`
` for FLOLAN
`
` for FLOLAN
` When used at room temperature,
`
`
` Freshly prepared reconstituted solutions
`
`
` (15°C to 25°C; 59°F to 77°F)
`or reconstituted solutions that have been
` reconstituted solutions:
`
`
`
` stored at 2°C to 8°C (36°F to 46°F) for
`
` • are stable for up to 8 hours
`
`
` no longer than 8 days can be
`
`
` following reconstitution or
` administered up to:
`
`
` removal from refrigerated
`
` • 72 hours at up to 25°C (77°F).
`
`
`
` storage
`
` • 48 hours at up to 30°C (86°F).
`
`• may be stored for up to 40
` • 24 hours at up to 35°C (95°F).
`
`
`
`
`
` hours refrigerated at 2°C to
` • 12 hours at up to 40°C (104°F).
`
`
` 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.
` • 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.
`
`
`
`
`Reference ID: 3733981
`
`
`
` 5
`
`
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`
`

`

`
`
`
`
`
`
`
`
`
` 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)]. 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.
`
`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.
`
`
`
`Reference ID: 3733981
`
`
`
` 6
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1103, p. 5 of 24
`
`

`

`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:
`
`
`
`
`Infusion Rate (mL/h) = [Dose (ng/kg/min) x Weight (kg) x 60 min/h]
`
`
`
`
`
`
`Final Concentration (ng/mL)
`
`Example calculations for infusion rates are as follows:
`Example 1: for a 60-kg person at the recommended initial dose of 2 ng/kg/min using a
`
`
`
`
`3,000-ng/mL concentration, the infusion rate would be as follows:
`
`
`
`
`
`
`Infusion Rate (mL/h) = [2 (ng/kg/min) x 60 (kg) x 60 (min/h)] = 2.4 (mL/h)
`
`
`
`
`
`
`3,000 (ng/mL)
`
`Example 2: for a 70-kg person at a dose of 16 ng/kg/min using a 15,000-ng/mL
`
`
`
`
`
`concentration, the infusion rate would be as follows:
`
`
`
`
`
`
`Infusion Rate (mL/h) = [16 (ng/kg/min) x 70 (kg) x 60 (min/h)] = 4.48 (mL/h)
`
`
`
`
`
`
`15,000 (ng/mL)
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`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.
`
`
`
`CONTRAINDICATIONS
`4
`
`
`
`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.
`
`
`Reference ID: 3733981
`
`
`
` 7
`
`
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`
`

`

`
`
`
`
`
`
` 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 (including interruptions in drug delivery) 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 [see Dosage and Administration
`
`
`
` (2.2)].
` Increased Risk for Bleeding
`
`
` 5.4
`
` 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 [see
`
`
`
` Clinical Pharmacology (12.3)].
`
`
`
`
`
` ADVERSE REACTIONS
` 6
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`Reference ID: 3733981
`
`
`
` 8
`
`
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`
`

`

`
`
`
`
`
`
`
`
`
` Table 3. 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
`
`
`
` Idiopathic or Heritable
`
` PAH
` Conventional
`
`
` Therapy
`
` (n = 54)
`
`
` 0%
` 15%
`
`
` 33%
`
` 11%
`
`
` 2%
` 31%
`
`
` 24%
`
`
` 30%
`
` 48%
` 6%
`
`
`
` -
`
` 13%
`
`
` 31%
`
` 9%
`
`
`
`
`
` PAH/SSD
`
`
` FLOLAN
`
` (n = 56)
`
`
` 75%
`
` 84%
`
` 46%
`
` 13%
`
`
` 23%
`
` 13%
`
` 43%
`
`
` 66%
`
` 41%
`
` 50%
`
`
` 39%
`
` 25%
`
`
` -
`
` 7%
`
`
`
`
` Conventional
`
` Therapy
`
` (n = 55)
`
`
` 0%
` 65%
`
` 5%
`
` 11%
`
`
`
` 0%
`
` 0%
` 42%
`
`
`
` 47%
`
` 16%
` 5%
`
`
`
` 24%
` 4%
`
`
`
` -
`
` 5%
`
`
`
`
` FLOLAN
`
` (n = 52)
`
`
` 54%
`
` 35%
`
` 83%
`
` 25%
`
`
` 42%
`
` 27%
`
` 35%
`
`
` 25%
`
` 67%
`
` 37%
`
`
` -
`
` 10%
`
`
` 44%
`
` 21%
`
`
`
`
`
` Adverse Reaction
`
` Body as a whole
`
` Jaw pain
` Nonspecific musculoskeletal pain
`
` Headache
` Chills/fever/sepsis/flu-like symptoms
`
` Cardiovascular system
`
` Flushing
`
` Hypotension
`
` Tachycardia
` Digestive system
`
` Anorexia
` Nausea/Vomiting
`
` Diarrhea
` Skin and Appendages
`
` Skin ulcer
` Eczema/rash/urticaria
`
` Musculoskeletal System
`
`
` Myalgia
` Nervous system
`
` Anxiety/hyperkinesias/nervousness
`
` /tremor
` Hyperesthesia/hypesthesia/paresthesia
`
` Dizziness
`
`
`
`
`
`
`
`
`
`
`
`
` 12%
`
` 83%
`
`
` 2%
` 70%
`
`
`
` 5%
` 59%
`
`
`
` 0%
` 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
`
`
`Reference ID: 3733981
`
`
`
` 9
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1103, p. 8 of 24
`
`

`

` 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.
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`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 (600 mcg/m2/day in rats, 2.5 times the recommended human dose, and
`
`
`
` 1,180 mcg/m2/day in rabbits, 4.8 times the recommended human dose based on body surface
`
`
`
`area) and have revealed no evidence of impaired fertility or harm to the fetus due to FLOLAN.
`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
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`Reference ID: 3733981
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`
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` 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.
`
`
`
`
`
` OVERDOSAGE
` 10
`
`
` 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.
`
`
`
`DESCRIPTION
`11
`
`
`
`
`
`
`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 (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. Epoprostenol sodium has a molecular weight of 374.45
`
`
`and a molecular formula of C20H31NaO5. The structural formula is:
`
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`Reference ID: 3733981
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` 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.
`
` • STERILE DILUENT for FLOLAN has sodium hydroxide added to adjust the pH to 10.2 to
`
`
`
`
` 10.8.
` • pH 12 STERILE DILUENT for FLOLAN has sodium hydroxide added to adjust the pH to
`
`
`
` 11.7 to 12.3.
`
`
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`
` 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 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.
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`Reference ID: 3733981
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` When other antiplatelet agents or anticoagulants are used concomitantly, there is a potential for
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`
`
` 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.
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`Reference ID: 3733981
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` NONCLINICAL TOXICOLOGY
` 13
`
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` 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).
`
`
`
`
`CLINICAL STUDIES
`14
`
`
`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 4 illustrates the treatment-related
`
`
`
`hemodynamic changes in these patients after 8 or 12 weeks of treatment.
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`Reference ID: 3733981
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` Table 4. Hemodynamics during Chronic Administration of FLOLAN in Patients with
`
`
` Idiopathic or Heritable PAH
`
`
`
`
`
`
`
` Hemodynamic
`
`
` Parameter
`
` Baseline
`
`Standard
`
` Therapy
`
` (n = 54)
`
`
` 2.0
`
`
`
`
` FLOLAN
`
`
`
` (n = 52)
` 2.0
`
`
`
` Mean Change from
`
` Baseline at End of
`
` Treatment Perioda
`Standard
`
` Therapy
`
` (n = 41)
`
`
` -0.1
`
`
`
` FLOLAN
`
`
`
` (n = 48)
` 0.3b
`
`
`
`
` 60
`
`
`
` 16
`
`
`
` 89
`
`
`
` 44
`
`
`
` 20
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
`
`
` 1
`
`
`
` -3
`
`
`
` -1
`
`
`
` 1
`
`
`
` 60
`
`
`
` 17
`
`
`
` 91
`
`
`
` 43
`
`
`
` 21
`
`
`
` -5b
`
`
`
` -4b
`
`
`
` -4
`
`
`
` 6b
`
`
`
` -5b
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` CI
`
`
` (L/min/m2)
`
` PAPm
` (mm Hg)
`
`
` PVR
`
` (Wood U)
` SAPm
`
`
` (mm Hg)
`
` SV
` (mL/beat)
`
` TPR
` (Wood U)
`
`
` 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, 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
`
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`Reference ID: 3733981
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` 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