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 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 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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