"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
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 (epoprostenol sodium) 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 (epoprostenol sodium) . 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||FLOLAN
(n = 391)
|Anxiety, nervousness, agitation||11%|
Adverse Events During Chronic Administration
Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of FLOLAN (epoprostenol sodium) (e.g., dizziness, syncope). Adverse events which may be 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 FLOLAN (epoprostenol sodium) . These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during FLOLAN (epoprostenol sodium) therapy, and a role for the drug in these events cannot be excluded.
Adverse Events During Chronic Administration for Idiopathic or Heritable PAH
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% greater on FLOLAN (epoprostenol sodium) in controlled trials.
Table 4: Adverse Events Regardless of Attribution Occurring
in Patients With Idiopathic or Heritable PAH With ≥ 10% Difference Between
FLOLAN (epoprostenol sodium) and Conventional Therapy Alone
(n = 52)
(n = 54)
|Occurrence More Common With FLOLAN|
|Nonspecific musculoskeletal pain||35%||15%|
|Hypesthesia, hyperesthesia, paresthesia||12%||2%|
Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving FLOLAN (epoprostenol sodium) .
Adverse Events During Chronic Administration for PAH/SSD
In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% greater on FLOLAN (epoprostenol sodium) in the controlled trial.
Table 5: Adverse Events Regardless of Attribution Occurring
in Patients with PAH/SSD With ≥ 10% Difference Between FLOLAN (epoprostenol sodium) and Conventional
(n = 56)
(n = 55)
|Occurrence More Common With FLOLAN|
|Skin and Appendages|
Although the relationship to FLOLAN (epoprostenol sodium) administration has not been established, pulmonary embolism has been reported in several patients taking FLOLAN (epoprostenol sodium) and there have been reports of hepatic failure.
Adverse Events Attributable to the Drug Delivery System
Chronic infusions of FLOLAN (epoprostenol sodium) 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 (epoprostenol sodium) . 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 (epoprostenol sodium) were associated with symptoms related to excess or insufficient FLOLAN (epoprostenol sodium) , 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 (epoprostenol sodium) . Because 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 (epoprostenol sodium) .
Endocrine and Metabolic: Hyperthyroidism.
Read the Flolan (epoprostenol sodium) Side Effects Center for a complete guide to possible side effects
Additional reductions in blood pressure may occur when FLOLAN (epoprostenol sodium) is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for FLOLAN (epoprostenol sodium) to increase the risk of bleeding. However, patients receiving infusions of FLOLAN (epoprostenol sodium) in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, FLOLAN (epoprostenol sodium) 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 (epoprostenol sodium) 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 (epoprostenol sodium) , which may be clinically significant in patients prone to digoxin toxicity.
Read the Flolan Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/24/2011
This monograph has been modified to include the generic and brand name in many instances.
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