Flolan (Epoprostenol Sodium) - Side Effects and Adverse Reactions

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	FLOLAN (n = 391)
Flushing	58%
Headache	49%
Nausea/vomiting	32%
Hypotension	16%
Anxiety, nervousness, agitation	11%
Chest pain	11%
Dizziness	8%
Bradycardia	5%
Abdominal pain	5%
Musculoskeletal pain	3%
Dyspnea	2%
Back pain	2%
Sweating	1%
Dyspepsia	1%
Hypesthesia/paresthesia	1%
Tachycardia	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 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
General
Chills/fever/sepsis/flu-like symptoms	25%	11%
Cardiovascular
Tachycardia	35%	24%
Flushing	42%	2%
Gastrointestinal
Diarrhea	37%	6%
Nausea/vomiting	67%	48%
Musculoskeletal
Jaw pain	54%	0%
Myalgia	44%	31%
Nonspecific musculoskeletal pain	35%	15%
Neurological
Anxiety/nervousness/tremor	21%	9%
Dizziness	83%	70%
Headache	83%	33%
Hypesthesia, hyperesthesia, paresthesia	12%	2%
Occurrence More Common With Standard Therapy
Cardiovascular
Heart failure	31%	52%
Syncope	13%	24%
Shock	0%	13%
Respiratory
Hypoxia	25%	37%

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.

Table 5. 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)
General
Asthenia	87%	81%
Cardiovascular
Angina pectoris	19%	20%
Arrhythmia	27%	20%
Bradycardia	15%	9%
Supraventricular tachycardia	8%	0%
Pallor	21%	30%
Cyanosis	31%	39%
Palpitation	63%	61%
Cerebrovascular accident	4%	0%
Hemorrhage	19%	11%
Hypotension	27%	31%
Myocardial ischemia	2%	6%
Gastrointestinal
Abdominal pain	27%	31%
Anorexia	25%	30%
Ascites	12%	17%
Constipation	6%	2%
Metabolic
Edema	60%	63%
Hypokalemia	6%	4%
Weight reduction	27%	24%
Weight gain	6%	4%
Musculoskeletal
Arthralgia	6%	0%
Bone pain	0%	4%
Chest pain	67%	65%
Neurological
Confusion	6%	11%
Convulsion	4%	0%
Depression	37%	44%
Insomnia	4%	4%
Respiratory
Cough increase	38%	46%
Dyspnea	90%	85%
Epistaxis	4%	2%
Pleural effusion	4%	2%
Skin and Appendages
Pruritus	4%	0%
Rash	10%	13%
Sweating	15%	20%
Special Senses
Amblyopia	8%	4%
Vision abnormality	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.

Table 6. Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With ≥10% Difference Between FLOLAN and Conventional Therapy Alone

Adverse Event	FLOLAN (n = 56)	Conventional Therapy (n = 55)
Occurrence More Common With FLOLAN
Cardiovascular
Flushing	23%	0%
Hypotension	13%	0%
Gastrointestinal
Anorexia	66%	47%
Nausea/vomiting	41%	16%
Diarrhea	50%	5%
Musculoskeletal
Jaw pain	75%	0%
Pain/neck pain/arthralgia	84%	65%
Neurological
Headache	46%	5%
Skin and Appendages
Skin ulcer	39%	24%
Eczema/rash/urticaria	25%	4%
Occurrence More Common With Conventional Therapy
Cardiovascular
Cyanosis	54%	80%
Pallor	32%	53%
Syncope	7%	20%
Gastrointestinal
Ascites	23%	33%
Esophageal reflux/gastritis	61%	73%
Metabolic
Weight decrease	45%	56%
Neurological
Dizziness	59%	76%
Respiratory
Hypoxia	55%	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.

Table 7. Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With <10% Difference Between FLOLAN and Conventional Therapy Alone

Adverse Event*	FLOLAN (n = 56)	Conventional Therapy (n = 55)
General
Asthenia	100%	98%
Hemorrhage/hemorrhage injection site/hemorrhage rectal	11%	2%
Infection/rhinitis	21%	20%
Chills/fever/sepsis/flu-like symptoms	13%	11%
Blood and Lymphatic
Thrombocytopenia	4%	0%
Cardiovascular
Heart failure/heart failure right	11%	13%
Myocardial Infarction	4%	0%
Palpitation	63%	71%
Shock	5%	5%
Tachycardia	43%	42%
Vascular disorder peripheral	96%	100%
Vascular disorder	95%	89%
Gastrointestinal
Abdominal enlargement	4%	0%
Abdominal pain	14%	7%
Constipation	4%	2%
Flatulence	5%	4%
Metabolic
Edema/edema peripheral/edema genital	79%	87%
Hypercalcemia	48%	51%
Hyperkalemia	4%	0%
Thirst	0%	4%
Musculoskeletal
Arthritis	52%	45%
Back pain	13%	5%
Chest pain	52%	45%
Cramps leg	5%	7%
Respiratory
Cough increase	82%	82%
Dyspnea	100%	100%
Epistaxis	9%	7%
Pharyngitis	5%	2%
Pleural effusion	7%	0%
Pneumonia	5%	0%
Pneumothorax	4%	0%
Pulmonary edema	4%	2%
Respiratory disorder	7%	4%
Sinusitis	4%	4%
Neurological
Anxiety/hyperkinesia/nervousness/tremor	7%	5%
Depression/depression psychotic	13%	4%
Hyperesthesia/hypesthesia/paresthesia	5%	0%
Insomnia	9%	0%
Somnolence	4%	2%
Skin and Appendages
Collagen disease	82%	84%
Pruritus	4%	2%
Sweat	41%	36%
Urogenital
Hematuria	5%	0%
Urinary tract infection	7%	0%

^*Adverse events that occurred in at least 2 patients in either treatment group.

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 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.

REPORTS OF SUSPECTED FLOLAN SIDE EFFECTS / ADVERSE REACTIONS

Possible Flolan side effects / adverse reactions in 54 year old female

Reported by a consumer/non-health professional from United States on 2011-10-05

Patient: 54 year old female weighing 58.0 kg (127.6 pounds)

Reactions: Gastrointestinal Haemorrhage, Urinary Tract Infection, Oesophageal Haemorrhage

Adverse event resulted in: hospitalization

Suspect drug(s):
Flolan

Other drugs received by patient: Depo-Provera; Oxycontin; Loperamide HCL; Pyridostigmine Bromide; Fludrocortisone Acetate; Triamcinolone; Zinc Sulfate; Lactulose; Acetaminophen; Cream; Potassium; Zofran; Neomycin; Furosemide; TPN; Macrobid; Oxycodone HCL; Albuterol; Lubriderm; Doxycycline; Midodrine Hydrochloride; Xifaxan; Sandostatin; Multi-Vitamin; Sildenafil Citrate; Keflex

Possible Flolan side effects / adverse reactions in 44 year old female

Reported by a consumer/non-health professional from United States on 2011-10-06

Patient: 44 year old female weighing 115.0 kg (253.0 pounds)

Reactions: Cardiac Failure, Pain in JAW

Adverse event resulted in: hospitalization

Suspect drug(s):
Flolan

Other drugs received by patient: Imodium; Risperidone; Bentyl; Mobic; Celexa; Naproxen (Aleve); Tramadol HCL; Revatio; Potassium; Gabapentin; Prilosec; Furosemide; Paxil CR

Possible Flolan side effects / adverse reactions in 60 year old female

Reported by a consumer/non-health professional from United States on 2011-10-07

Patient: 60 year old female

Reactions: Eye Operation, Adverse Event, Infection

Adverse event resulted in: hospitalization

Suspect drug(s):
Flolan

Other drugs received by patient: Revatio; Coumadin