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Flolan Side Effects, and Drug Interactions - Epoprostenol sodium

Flolan Side Effects, and Drug Interactions - Epoprostenol sodium

 

SIDE EFFECTS

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-per-minute 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 the major pharmacologic effect of FLOLAN, vasodilation. The most common dose-limiting adverse events (occurring in ³ 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 ³ 1% of Patients	FLOLAN (n = 391)
Flushing	58%
Headache	49%
Nauses/Vomiting	32%
Hypotension	16%
Anxiety, nervousness, agitation	11%
Chest pain	11%
Dizziness	8%
Bradycardia	5%
Abdominal pain	5%
Musculoskeletal pain	3%
Dyspnes	2%
Back pain	2%
Sweating	1%
Dyspepsia	1%
Hypesthesia/Paresthesia	1%
Tachycardia	1%

Adverse Events During Chrouic 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 two groups in controlled trials for PPH.

Table 4: Adverse Events Regardless of Attribution Occurring in Patients with PPH with ³ 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 Flushing	35% 42%	24% 2%
GASTROINTESTINAL
Diarrhea Nausea/vomiting	37% 67%	6% 48%
MUSCULOSKELETAL
Jaw Pain Myalgia Nonspecifi musculoskoletal pain	54% 44% 35%	0% 31% 15%
NEUROLOGICAL
Anxiety/nervousness/tremor Dizziness Headache Hypesthesia, Hyperesthosia, Paresthesia	21% 83% 83% 12%	9% 70% 33% 2%
Occurrence More Common with Conventional Therapy
CARDIOVASCULAR
Heart Failure Syncope Shock	31% 13% 0%	52% 24% 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	FOLAN	Conventional Therapy
GENERAL Asthenia	(n = 52) 87%	(n = 54) 81%
CARDIOVASCULAR
Angina pectoris Arrhythmia Bradycardia Supraventricular tachycardia Pallor Cyanosis Palpitation Cerebrovascular accident Hemorrhage Hypotension Myocardiul ischemis	19% 27% 15% 8% 21% 31% 63% 4% 19% 27% 2%	20% 20% 9% 0% 30% 39% 61% 0% 11% 31% 6%
GASTRONTESTINAL
Abdominal pain Anorexia Ascites Constipation	27% 25% 12% 6%	31% 30% 17% 2%
METABOLIC
Edems Hypokalemia Weight reduction Weight gain	60% 6% 27% 6%	63% 4% 24% 49%
MUSCULOSKELETAL
Arthralgia Bone pain Chest pain	6% 0% 67%	0% 4% 65%
NEUROLOGICAL
Confusion Convulsion Depression Insomnis	6% 4% 37% 4%	11% 0% 44% 4%
RESPIRATORY
Cough increase Dyspnea Eplistaxis Pleural effusion	38% 90% 4% 4%	46% 85% 2% 2%
SKIN AND APPENDAGES
Pruritus Rash Sweating	4% 10% 15%	0% 13% 20%
SPECIAL SENSES
Amblyopin Vision abnormality	8% 4%	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 two groups in controlled trial for patients with PH/SSD.

Table 6: Adverse Events Regardless of Attribution Occurring in Patients with PH/SSD with ³ 10% Difference Between FLOLAN and Conventional Therapy Alone

Adverse Event	FLOLAN (n = 56)	Conventional Therapy (n = 55)
Occurrence More Common with FLOLAN
CARDIOVASCULAR
Flushing Hypotension	23% 13%	0% 0%
GASTROINTESTINAL
Anorexia Nausea/vomiting Diarrhea	66% 41% 50%	47% 16% 5%
MUSCULOSKELETAL
Jaw pain Pain/neck pain/arthralgia	75% 84%	0% 65%
NEUROLOGICAL Headache	46%	5%
SKIN AND APPENDAGES Skin ulcer Eczema/rash/urticarix	39% 25%	54% 4%
Occurrence More Common with Conventional Therapy
CARDIOVASCULAR
Cyanosis Pailor Syncope	54% 32% 7%	80% 53% 20%
GASTROINTESTINAL
Ascites Esophageal reflux/gastritis	23% 61%	33% 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 Thearpy (n = 55)
GENERAL
Asthenia Hemorrhage/hemorrhage injection Site/hemorrhage rectal Infection/rhimitis Chills/fever/sepsis/flu-like symptoms	100% 11% 21% 13%	98% 2% 20% 11%
BLOOD AND LYMPHATICS
Thrombocytopenia	4%	0%
CARDIOVASCULAR
Heart failure/heart failure right Myocardial Infarction Palpitation Shock Tachycardia Thrombocytopenia Vascular disorder peripheral Vascular disorder	11% 4% 63% 5% 43% 4% 96% 95%	13% 0% 71% 5% 42% 0% 100% 89%
GASTROINTESTINAL
Abdominal enlargement Abdominal pain Constipation Fatulence	4% 14% 4% 5%	0% 7% 2% 4%
METABOLIC
Edema/edema peripheral/edema genital Hypercalccmia Hyperkalemia Thirst	79% 48% 4% 0%	87% 51% 0% 4%
MUSCULOSKELETAL
Arthritis Back pain Chest pain Cramps leg	52% 13% 52% 5%	45% 5% 45% 7%
RESPIRATORY
Cough increase Dyspnea Epistaxis Pharyngitis Pleural effusion Pneumonia Pneumothorix Pulmonary edema Respiratory disorder Sinusitis	82% 100% 9% 5% 7% 5% 4% 4% 7% 4%	82% 10% 7% 2% 0% 0% 0% 2% 4% 4%
NEUROLOGICAL
Anxiety/hyperkinesia/nervousness/tremor Depression/depression psychotic Hyperesthesia/hypesthesia/paresthesia Insomnia Somnolence	7% 13% 5% 9% 4%	5% 4% 0% 0% 2%
SKIN AND APPENDAGES
Collagen disease Pruritus Sweat	82% 4% 41%	84% 2% 36%
UROGENITAL
Hemuluria Urinary tract infection	5% 7%	0% 0%

*Table lists adverse events which 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 and pancytopenia.

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 to13% of patients pain at the injection site. During 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 per 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).

DRUG INTERACTIONS

Additional reductions in blood pressure may occur when FLOLAN is administered with diuretics, antiyopertensive 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 anticogulants without evidence of increased bleeding. In clinical trials, FLOLAN was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen. 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 per day [600 mcg/m² per day, 2.5 times the recommended human dose (4.6 ng/kg per minute or 245.1 mcg/m² per 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 per day (600 mcg/m² per day in rats, 2.5 times the recommended human dose, and 1180 mcg/m² per 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 caesarean 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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