FLOLAN®
`(epoprostenol sodium)
`for Injection
`
`PRESCRIBING INFORMATION
`
`DESCRIPTION
`FLOLAN (epoprostenol sodium) for Injection is a sterile sodium salt 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, 2.93 mg
`sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.
`Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally
`occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet
`aggregation.
`Epoprostenol is (5Z,9a,11a,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid.
`Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of
`C20H31NaO5. The structural formula is:
`
`FLOLAN is a white to off-white powder that must be reconstituted with STERILE DILUENT
`for FLOLAN. STERILE DILUENT for FLOLAN is supplied in glass vials containing 50 mL of
`94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for
`Injection, USP.
`The reconstituted solution of FLOLAN has a pH of 10.2 to 10.8 and is increasingly unstable
`at a lower pH.
`
`CLINICAL PHARMACOLOGY
`General: Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of
`pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In
`animals, the vasodilatory effects reduce right- and left-ventricular afterload and increase cardiac
`output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose.
`At low doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol causes
`reflex tachycardia in response to direct vasodilation and hypotension. No major effects on
`cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in
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`animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric
`emptying.
`Pharmacokinetics: Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also
`subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have
`indicated a high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and a
`short half-life (2.7 minutes). During infusions in animals, steady-state plasma concentrations of
`tritium-labeled epoprostenol were reached within 15 minutes and were proportional to infusion
`rates.
`No available chemical assay is sufficiently sensitive and specific to assess the in vivo human
`pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C
`and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans
`is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol
`in human plasma, based on inhibition of platelet aggregation, was similar for males (n = 954) and
`females (n = 1,024).
`Tritium-labeled epoprostenol has been administered to humans in order to identify the
`metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites:
`6-keto-PGF1a (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1a
`(enzymatically formed), both of which have pharmacological activity orders of magnitude less
`than epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a
`1-week period was 82% and 4% of the administered dose, respectively. Fourteen additional
`minor metabolites have been isolated from urine, indicating that epoprostenol is extensively
`metabolized in humans.
`
`CLINICAL TRIALS IN PULMONARY HYPERTENSION
`Acute Hemodynamic Effects: Acute intravenous infusions of FLOLAN for up to 15 minutes
`in patients with secondary and primary pulmonary hypertension 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.
`Chronic Infusion in Primary Pulmonary Hypertension (PPH): Hemodynamic
`Effects: Chronic continuous infusions of FLOLAN in patients with PPH were studied in
`2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing FLOLAN plus
`conventional therapy to conventional therapy alone. Dosage of FLOLAN was determined as
`described in DOSAGE AND ADMINISTRATION and averaged 9.2 ng/kg/min at study’s end.
`Conventional therapy varied among patients and included some or all of the following:
`anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to
`two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New
`York Heart Association (NYHA) functional Class II patients, all patients were either functional
`Class III or Class IV. As results were similar in the 2 studies, the pooled results are described.
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`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 to those who did not. Table 1 illustrates the treatment-related
`hemodynamic changes in these patients after 8 or 12 weeks of treatment.
`
`Table 1. Hemodynamics During Chronic Administration of FLOLAN in Patients
`With PPH
`
`Baseline
`
`Hemodynamic
`Parameter
`
`FLOLAN
`(N = 52)
`2.0
`
`Mean Change from Baseline
`at End of Treatment Period*
`Standard
`Therapy
`(N = 41)
`-0.1
`
`FLOLAN
`(N = 48)
`0.3†
`
`Standard
`Therapy
`(N = 54)
`2.0
`
`CI
`(L/min/m2)
`PAPm
`(mm Hg)
`PVR
`(Wood U)
`SAPm
`(mm Hg)
`SV
`(mL/beat)
`TPR
`(Wood U)
`* 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).
`† Denotes statistically significant difference between FLOLAN and conventional therapy groups.
`CI = cardiac index, PAPm = mean pulmonary arterial pressure, PVR = pulmonary vascular
`resistance, SAPm = mean systemic arterial pressure, SV = stroke volume, TPR = total
`pulmonary resistance.
`
`60
`
`16
`
`89
`
`44
`
`20
`
`60
`
`17
`
`91
`
`43
`
`21
`
`-5†
`
`-4†
`
`-4
`
`6†
`
`-5†
`
`1
`
`1
`
`-3
`
`-1
`
`1
`
`These hemodynamic improvements appeared to persist when FLOLAN was administered for
`at least 36 months in an open, nonrandomized study.
`Clinical Effects: Statistically significant improvement was observed in exercise capacity, as
`measured by the 6-minute walk test in patients receiving continuous intravenous FLOLAN plus
`conventional therapy (N = 52) for 8 or 12 weeks compared to those receiving conventional
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`therapy alone (N = 54). Improvements were apparent as early as the first week of therapy.
`Increases in exercise capacity were accompanied by statistically significant improvement in
`dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea
`Fatigue Index.
`Survival was improved in NYHA functional Class III and Class IV PPH patients treated with
`FLOLAN for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the
`treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas
`none of the 41 patients receiving FLOLAN died (p = 0.003).
`Chronic Infusion in Pulmonary Hypertension Associated with the Scleroderma
`Spectrum of Diseases (PH/SSD): Hemodynamic Effects: Chronic continuous infusions
`of FLOLAN in patients with PH/SSD were studied in a prospective, open, randomized trial of
`12 weeks’ duration comparing FLOLAN plus conventional therapy (N = 56) to conventional
`therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either
`functional Class III or Class IV. Dosage of FLOLAN was determined as described in DOSAGE
`AND ADMINISTRATION and averaged 11.2 ng/kg/min at study’s end. Conventional therapy
`varied among patients and included some or all of the following: anticoagulants in essentially all
`patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40%
`of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and
`statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment
`were observed in patients who received FLOLAN chronically compared to those who did not.
`Table 2 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of
`treatment.
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`Table 2. Hemodynamics During Chronic Administration of FLOLAN in Patients With
`PH/SSD
`
`Hemodynamic
`Parameter
`
`Baseline
`Conventional
`Therapy
`(N = 55)
`2.2
`
`FLOLAN
`(N = 56)
`1.9
`
`Mean Change from
`Baseline at 12 Weeks
`Conventional
`Therapy
`(N = 48)
`-0.1
`
`FLOLAN
`(N = 50)
`0.5*
`
`51
`
`13
`
`14
`
`93
`
`49
`
`11
`
`11
`
`89
`
`-5*
`
`-1*
`
`-5*
`
`-8*
`
`1
`
`1
`
`1
`
`-1
`
`CI
`(L/min/m2)
`PAPm
`(mm Hg)
`RAPm
`(mm Hg)
`PVR
`(Wood U)
`SAPm
`(mm Hg)
`* Denotes statistically significant difference between FLOLAN and conventional therapy groups
`(N is the number of patients with hemodynamic data).
`CI = cardiac index, PAPm = mean pulmonary arterial pressure, RAPm = mean right arterial
`pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure.
`
`Clinical Effects: Statistically significant improvement was observed in exercise capacity, as
`measured by the 6-minute walk, in patients receiving continuous intravenous FLOLAN plus
`conventional therapy for 12 weeks compared to those receiving conventional therapy alone.
`Improvements were apparent in some patients at the end of the first week of therapy. Increases in
`exercise capacity were accompanied by statistically significant improvements in dyspnea and
`fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12,
`NYHA functional class improved in 21 of 51 (41%) patients treated with FLOLAN compared to
`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. Of the patients randomized, NYHA functional class data
`at 12 weeks were not available for 5 patients treated with FLOLAN and 7 patients treated with
`conventional therapy alone.
`No statistical difference in survival over 12 weeks was observed in PH/SSD patients treated
`with FLOLAN as compared to 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.
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`No controlled clinical trials with FLOLAN have been performed in patients with pulmonary
`hypertension associated with other diseases.
`
`INDICATIONS AND USAGE
`FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary
`hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease
`in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy
`(see CLINICAL TRIALS IN PULMONARY HYPERTENSION).
`
`CONTRAINDICATIONS
`A large study 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 congestive heart failure due to severe left
`ventricular systolic dysfunction is therefore contraindicated.
`Some patients with pulmonary hypertension have developed pulmonary edema during dose
`initiation, which may be associated with pulmonary veno-occlusive disease. FLOLAN should
`not be used chronically in patients who develop pulmonary edema during dose initiation.
`FLOLAN is also contraindicated in patients with known hypersensitivity to the drug or to
`structurally related compounds.
`
`WARNINGS
`FLOLAN must be reconstituted only as directed using STERILE DILUENT for
`FLOLAN. FLOLAN must not be reconstituted or mixed with any other parenteral
`medications or solutions prior to or during administration.
`Abrupt Withdrawal: Abrupt withdrawal (including interruptions in drug delivery) or sudden
`large reductions in dosage of FLOLAN may result in symptoms associated with rebound
`pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one
`Class III PPH patient's death was judged attributable to the interruption of FLOLAN. Abrupt
`withdrawal should be avoided.
`Sepsis: See ADVERSE REACTIONS: Adverse Events Attributable to the Drug Delivery
`System.
`
`PRECAUTIONS
`General: FLOLAN should be used only by clinicians experienced in the diagnosis and
`treatment of pulmonary hypertension. The diagnosis of PPH or PH/SSD should be carefully
`established.
`FLOLAN is a potent pulmonary and systemic vasodilator. Dose initiation with FLOLAN must
`be performed in a setting with adequate personnel and equipment for physiologic monitoring and
`emergency care. Dose initiation in controlled PPH clinical trials was performed during right
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`heart catheterization. In uncontrolled PPH and controlled PH/SSD clinical trials, dose initiation
`was performed without cardiac catheterization. The risk of cardiac catheterization in patients
`with pulmonary hypertension should be carefully weighed against the potential benefits. During
`dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in
`cardiac output occurred rarely. In such cases, dose reduction should be considered, but such an
`increase does not imply that chronic treatment is contraindicated.
`During chronic use, FLOLAN is delivered continuously on an ambulatory basis through a
`permanent indwelling central venous catheter. Unless contraindicated, anticoagulant therapy
`should be administered to PPH and PH/SSD patients receiving FLOLAN to reduce the risk of
`pulmonary thromboembolism or systemic embolism through a patent foramen ovale. In order to
`reduce the risk of infection, aseptic technique must be used in the reconstitution and
`administration of FLOLAN as well as in routine catheter care. Because FLOLAN is metabolized
`rapidly, even brief interruptions in the delivery of FLOLAN may result in symptoms associated
`with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. The decision
`to initiate therapy with FLOLAN should be based upon the understanding that there is a high
`likelihood that intravenous therapy with FLOLAN will be needed for prolonged periods,
`possibly years, and the patient's ability to accept and care for a permanent intravenous catheter
`and infusion pump should be carefully considered.
`Based on clinical trials, the acute hemodynamic response to FLOLAN did not correlate well
`with improvement in exercise tolerance or survival during chronic use of FLOLAN. Dosage of
`FLOLAN during chronic use should be adjusted at the first sign of recurrence or worsening of
`symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated
`with FLOLAN (see DOSAGE AND ADMINISTRATION). Following dosage adjustments,
`standing and supine blood pressure and heart rate should be monitored closely for several hours.
`Information for Patients: Patients receiving FLOLAN should receive the following
`information. FLOLAN must be reconstituted only with STERILE DILUENT for FLOLAN.
`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.
`Sterile technique must be adhered to in preparing the drug and in the care of the catheter, and
`even brief interruptions in the delivery of 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. The patient's ability to accept and care for a permanent intravenous catheter and
`infusion pump should also be carefully considered.
`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 the 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. In clinical
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`trials, FLOLAN was used with digoxin, diuretics, anticoagulants, oral vasodilators, and
`supplemental oxygen.
`In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide
`or digoxin in whom therapy with FLOLAN was initiated, apparent oral clearance values for
`furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the
`second day of therapy and had returned to baseline values by day 87. The change in furosemide
`clearance value is not likely to be clinically significant. However, patients on digoxin may show
`elevations of digoxin concentrations after initiation of therapy with FLOLAN, which may be
`clinically significant in patients prone to digoxin toxicity.
`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).
`Pregnancy: Pregnancy Category B. Reproductive studies have been performed in pregnant rats
`and rabbits at doses up to 100 mcg/kg/day (600 mcg/m2/day in rats, 2.5 times the recommended
`human dose, and 1,180 mcg/m2/day in rabbits, 4.8 times the recommended human dose based on
`body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to
`FLOLAN. There are, however, no adequate and well-controlled studies in pregnant women.
`Because animal reproduction studies are not always predictive of human response, this drug
`should be used during pregnancy only if clearly needed.
`Labor and Delivery: The use of FLOLAN during labor, vaginal delivery, or cesarean section
`has not been adequately studied in humans.
`Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many
`drugs are excreted in human milk, caution should be exercised when FLOLAN is administered to
`a nursing woman.
`Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
`Geriatric Use: Clinical studies of FLOLAN in pulmonary hypertension did not include
`sufficient numbers of subjects aged 65 and over to determine whether they respond differently
`from younger patients. Other reported clinical experience has not identified differences in
`responses between the elderly and younger patients. In general, dose selection for an elderly
`patient should be cautious, usually starting at the low end of the dosing range, reflecting the
`greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or
`other drug therapy.
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`ADVERSE REACTIONS
`During clinical trials, adverse events were classified as follows: (1) adverse events during
`dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events
`associated with the drug delivery system.
`Adverse Events During Dose Initiation and Escalation: During early clinical trials,
`FLOLAN was increased in 2-ng/kg/min increments until the patients developed symptomatic
`intolerance. The most common adverse events and the adverse events that limited further
`increases in dose were generally related to vasodilation, the major pharmacologic effect of
`FLOLAN. The most common dose-limiting adverse events (occurring in ‡1% of patients) were
`nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety,
`dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 3
`lists the adverse events reported during dose initiation and escalation in decreasing order of
`frequency.
`
`Table 3. Adverse Events During Dose Initiation and Escalation
`
`Adverse Events Occurring
`in =1% of Patients
`
`Flushing
`Headache
`Nausea/vomiting
`Hypotension
`Anxiety, nervousness, agitation
`Chest pain
`Dizziness
`Bradycardia
`Abdominal pain
`Musculoskeletal pain
`Dyspnea
`Back pain
`Sweating
`Dyspepsia
`Hypesthesia/paresthesia
`Tachycardia
`
`FLOLAN
`(n = 391)
`58%
`49%
`32%
`16%
`11%
`11%
`8%
`5%
`5%
`3%
`2%
`2%
`1%
`1%
`1%
`1%
`
`Adverse Events During Chronic Administration: Interpretation of adverse events is
`complicated by the clinical features of PPH and PH/SSD, which are similar to some of the
`pharmacologic effects of FLOLAN (e.g., dizziness, syncope). Adverse events probably related to
`the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular
`failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to
`
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`FLOLAN. These include headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like
`symptoms, and anxiety/nervousness.
`Adverse Events During Chronic Administration for PPH: In an effort to separate the
`adverse effects of the drug from the adverse effects of the underlying disease, Table 4 lists
`adverse events that occurred at a rate at least 10% different in the 2 groups in controlled trials for
`PPH.
`
`Table 4. Adverse Events Regardless of Attribution Occurring in Patients With PPH With
`=10% Difference Between FLOLAN and Conventional Therapy Alone
`
`Adverse Event
`
`FLOLAN
`(n = 52)
`
`Conventional
`Therapy
`(n = 54)
`
`Occurrence More Common With FLOLAN
`
`25%
`
`35%
`42%
`
`37%
`67%
`
`54%
`44%
`35%
`
`General
`Chills/fever/sepsis/flu-like symptoms
`Cardiovascular
`Tachycardia
`Flushing
`Gastrointestinal
`Diarrhea
`Nausea/vomiting
`Musculoskeletal
`Jaw pain
`Myalgia
`Nonspecific musculoskeletal pain
`Neurological
`21%
`Anxiety/nervousness/tremor
`83%
`Dizziness
`83%
`Headache
`12%
`Hypesthesia, hyperesthesia, paresthesia
`Occurrence More Common With Standard Therapy
`Cardiovascular
`Heart failure
`Syncope
`Shock
`Respiratory
`Hypoxia
`
`31%
`13%
`0%
`
`25%
`
`10
`
`11%
`
`24%
`2%
`
`6%
`48%
`
`0%
`31%
`15%
`
`9%
`70%
`33%
`2%
`
`52%
`24%
`13%
`
`37%
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`Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving
`FLOLAN.
`Table 5 lists additional adverse events reported in PPH patients receiving FLOLAN plus
`conventional therapy or conventional therapy alone during controlled clinical trials.
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`Table 5. Adverse Events Regardless of Attribution Occurring in Patients With PPH
`With <10% Difference Between FLOLAN and Conventional Therapy Alone
`
`Adverse Event
`
`General
`Asthenia
`Cardiovascular
`Angina pectoris
`Arrhythmia
`Bradycardia
`Supraventricular tachycardia
`Pallor
`Cyanosis
`Palpitation
`Cerebrovascular accident
`Hemorrhage
`Hypotension
`Myocardial ischemia
`Gastrointestinal
`Abdominal pain
`Anorexia
`Ascites
`Constipation
`Metabolic
`Edema
`Hypokalemia
`Weight reduction
`Weight gain
`Musculoskeletal
`Arthralgia
`Bone pain
`Chest pain
`Neurological
`Confusion
`Convulsion
`Depression
`Insomnia
`Respiratory
`Cough increase
`
`FLOLAN
`(n = 52)
`
`Conventional Therapy
`(n = 54)
`
`81%
`
`20%
`20%
`9%
`0%
`30%
`39%
`61%
`0%
`11%
`31%
`6%
`
`31%
`30%
`17%
`2%
`
`63%
`4%
`24%
`4%
`
`0%
`4%
`65%
`
`11%
`0%
`44%
`4%
`
`46%
`
`87%
`
`19%
`27%
`15%
`8%
`21%
`31%
`63%
`4%
`19%
`27%
`2%
`
`27%
`25%
`12%
`6%
`
`60%
`6%
`27%
`6%
`
`6%
`0%
`67%
`
`6%
`4%
`37%
`4%
`
`38%
`
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`Dyspnea
`Epistaxis
`Pleural effusion
`Skin and Appendages
`Pruritus
`Rash
`Sweating
`Special Senses
`Amblyopia
`Vision abnormality
`
`90%
`4%
`4%
`
`4%
`10%
`15%
`
`8%
`4%
`
`85%
`2%
`2%
`
`0%
`13%
`20%
`
`4%
`0%
`
`Adverse Events During Chronic Administration for PH/SSD: In an effort to separate
`the adverse effects of the drug from the adverse effects of the underlying disease, Table 6 lists
`adverse events that occurred at a rate at least 10% different in the 2 groups in the controlled trial
`for patients with PH/SSD.
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`

`Table 6. Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD
`With =10% Difference Between FLOLAN and Conventional Therapy Alone
`
`FLOLAN
`(n = 56)
`Adverse Event
`Occurrence More Common With FLOLAN
`
`Conventional Therapy
`(n = 55)
`
`0%
`0%
`
`47%
`16%
`5%
`
`0%
`65%
`
`5%
`
`Cardiovascular
`Flushing
`Hypotension
`Gastrointestinal
`Anorexia
`Nausea/vomiting
`Diarrhea
`Musculoskeletal
`Jaw pain
`Pain/neck pain/arthralgia
`Neurological
`Headache
`Skin and Appendages
`24%
`39%
`Skin ulcer
`4%
`25%
`Eczema/rash/urticaria
`Occurrence More Common With Conventional Therapy
`Cardiovascular
`Cyanosis
`Pallor
`Syncope
`Gastrointestinal
`Ascites
`Esophageal reflux/gastritis
`Metabolic
`Weight decrease
`Neurological
`Dizziness
`Respiratory
`Hypoxia
`
`23%
`13%
`
`66%
`41%
`50%
`
`75%
`84%
`
`46%
`
`54%
`32%
`7%
`
`23%
`61%
`
`45%
`
`59%
`
`55%
`
`80%
`53%
`20%
`
`33%
`73%
`
`56%
`
`76%
`
`65%
`
`Table 7 lists additional adverse events reported in PH/SSD patients receiving FLOLAN plus
`conventional therapy or conventional therapy alone during controlled clinical trials.
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`Table 7. Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD
`With <10% Difference Between FLOLAN and Conventional Therapy Alone
`
`Adverse Event*
`
`General
`Asthenia
`Hemorrhage/hemorrhage
`injection site/hemorrhage rectal
`Infection/rhinitis
`Chills/fever/sepsis/flu-like symptoms
`Blood and Lymphatic
`Thrombocytopenia
`Cardiovascular
`Heart failure/heart failure right
`Myocardial Infarction
`Palpitation
`Shock
`Tachycardia
`Vascular disorder peripheral
`Vascular disorder
`Gastrointestinal
`Abdominal enlargement
`Abdominal pain
`Constipation
`Flatulence
`Metabolic
`Edema/edema peripheral/edema genital
`Hypercalcemia
`Hyperkalemia
`Thirst
`Musculoskeletal
`Arthritis
`Back pain
`Chest pain
`Cramps leg
`Respiratory
`Cough increase
`Dyspnea
`Epistaxis
`
`FLOLAN
`(n = 56)
`
`Conventional Therapy
`(n = 55)
`
`98%
`2%
`
`20%
`11%
`
`0%
`
`13%
`0%
`71%
`5%
`42%
`100%
`89%
`
`0%
`7%
`2%
`4%
`
`87%
`51%
`0%
`4%
`
`45%
`5%
`45%
`7%
`
`82%
`100%
`7%
`
`100%
`11%
`
`21%
`13%
`
`4%
`
`11%
`4%
`63%
`5%
`43%
`96%
`95%
`
`4%
`14%
`4%
`5%
`
`79%
`48%
`4%
`0%
`
`52%
`13%
`52%
`5%
`
`82%
`100%
`9%
`
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`Pharyngitis
`Pleural effusion
`Pneumonia
`Pneumothorax
`Pulmonary edema
`Respiratory disorder
`Sinusitis
`Neurological
`Anxiety/hyperkinesia/nervousness/tremor
`Depression/depression psychotic
`Hyperesthesia/hypesthesia/paresthesia
`Insomnia
`Somnolence
`Skin and Appendages
`Collagen disease
`Pruritus
`Sweat
`Urogenital
`0%
`5%
`Hematuria
`0%
`7%
`Urinary tract infection
`*Adverse events that occurred in at least 2 patients in either treatment group.
`
`2%
`0%
`0%
`0%
`2%
`4%
`4%
`
`5%
`4%
`0%
`0%
`2%
`
`84%
`2%
`36%
`
`5%
`7%
`5%
`4%
`4%
`7%
`4%
`
`7%
`13%
`5%
`9%
`4%
`
`82%
`4%
`41%
`
`Although the relationship to FLOLAN administration has not been established, pulmonary
`embolism has been reported in several patients taking FLOLAN and there have been reports of
`hepatic failure.
`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 PPH trials of up to 12 weeks’ duration, up to 21% of patients
`reported a local infection and up to 13% of patients reported pain at the injection site. During a
`controlled PH/SSD trial of 12 weeks’ duration, 14% of patients reported a local infection and 9%
`of patients reported pain at the injection site. During long-term follow-up in the clinical trial of
`PPH, sepsis was reported at least once in 14% of patients and occurred at a rate of
`0.32 infections/patient per year in patients treated with FLOLAN. This rate was higher than
`reported in patients using chronic indwelling central venous catheters to administer parenteral
`nutrition, but lower than reported in oncology patients using these catheters. Malfunctions in the
`delivery system resulting in an inadvertent bolus of or a reduction in FLOLAN were associated
`with symptoms related to excess or insufficient FLOLAN, respectively (see ADVERSE
`REACTIONS: Adverse Events During Chronic Administration).
`Observed During Clinical Practice: In addition to adverse reactions reported from clinical
`trials, the following events have been identified during post-approval use of FLOLAN. Because
`
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`they are reported voluntarily from a population of unknown size, estimates of frequency cannot
`be made. These events have been chosen for inclusion due to a combination of their seriousness,
`frequency of reporting, or potential causal connection to FLOLAN.
`Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly.
`Endocrine and Metabolic: Hyperthyroidism.
`
`OVERDOSAGE
`Signs and symptoms of excessive doses of FLOLAN during clinical trials are the expected
`dose-limiting pharmacologic effects of FLOLAN, including flushing, headache, hypotension,
`tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of
`FLOLAN.
`One patient with secondary pulmonary hypertension 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. In clinical practice, fatal occurrences of hypoxemia, hypotension,
`and respiratory arrest have been reported following overdosage of FLOLAN.
`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.
`
`DOSAGE AND ADMINISTRATION
`Important Note: FLOLAN must be reconstituted only with STERILE DILUENT for
`FLOLAN. Reconstituted solutions of FLOLAN must not be diluted or administered with other
`parenteral solutions or medications (see WARNINGS).
`Dosage: Continuous chronic infusion of FLOLAN should be administered through a central
`venous catheter. Temporary peripheral intravenous infusion may be used until central access is
`established. Chronic infusion of FLOLAN should be initiated at 2 ng/kg/min and increased in
`increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects
`are elicited or until a tolerance limit to the drug is established and further increases in the
`infusion rate are not clinically warranted (see Dosage Adjustments). If dose-limiting
`pharmacologic effects occur, then the infusion rate should be decreased to an appropriate chronic
`infusion rate whereby the pharmacologic effects of FLOLAN are tolerated. In clinical trials, the
`most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis,
`headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were
`not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, a lower dose that is
`tolerated by the patient should be identified.
`In the controlled 12-week trial in PH/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.
`
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`Dosage Adjustments: Changes in the chronic infusion rate should be based on persistence,
`recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the
`occurrence of adverse events due to excessive doses of FLOLAN. In general, increases in dose
`from the initial chronic dose should be expected.
`Increments in dose should be considered if symptoms of pulmonary hypert