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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions during: Dose Initiation and Escalation: Nausea, vomiting, headache, hypotension, flushing, chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Chronic Dosing: Headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GENERAMEDIX MEDICAL AFFAIRS at tel:1-866-436-3721 and or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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, epoprostenol 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 epoprostenol. 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 4 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency. Table 4: Adverse Events During Dose Initiation and Escalation Adverse Events Occurring in ≥1% of Patients Epoprostenol (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 for PPH 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 epoprostenol (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 epoprostenol. These include headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousness. 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% different in the 2 groups in controlled trials for PPH. Table 5: Adverse Events Regardless of Attributions Occurring in Patients With PPH With ≥ 10% Difference Between Epoprostenol and Conventional Therapy Alone Occurrence More Common With Epoprostenol 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 epoprostenol. Table 6 lists additional adverse events reported in PPH patients receiving epoprostenol plus conventional therapy or conventional therapy alone during controlled clinical trials. Table 6: Adverse Events Regardless of Attribution Occurring In Patients with PPH With <10% Difference between Epoprostenol and Conventional Therapy Adverse Event Epoprostenol (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 4% 0% Pruritus 10% 13% Rash 15% 20% Sweating 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 7 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 7: Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With ≥10% Difference Between Epoprostenol and Conventional Therapy Alone Adverse Event Epoprostenol (n = 56) Conventional Therapy (n = 55) Occurrence More Common With Epoprostenol 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 8 lists additional adverse events reported in PH/SSD patients receiving epoprostenol plus conventional therapy or conventional therapy alone during controlled clinical trials. Table 8: Adverse Events Regardless of Attribution Occurring in Patients With PH/SSD With <10% Difference Between Epoprostenol and Conventional Therapy Alone Adverse Event* Epoprostenol (n = 56) Conventional Therapy (n = 55) *Adverse events that occurred in at least 2 patients in either treatment group. General Asthenia 100% 98% Hemorrhage/hemorrhageinjection 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% 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% Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure. Adverse Events Attributable to the Drug Delivery System Chronic infusions of epoprostenol 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 epoprostenol. 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 epoprostenol were associated with symptoms related to excess or insufficient epoprostenol, respectively [see ADVERSE REACTIONS, Clinical Trials Experience, Adverse Events During Chronic Administration for PPH ( 6.1 ) ]. 6.2 Post-Marketing Experience In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of epoprostenol. 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 epoprostenol. Blood and Lymphatic: Anemia, hypersplenism, pancytopenia, splenomegaly. Endocrine and Metabolic: Hyperthyroidism.