Epsilon Aminocaproic Acid
Action And Clinical Pharmacology: Epsilon aminocaproic acid is a monoaminocarboxylic acid which acts as an effective inhibitor of fibrinolysis. The beneficial fibrinolysis-inhibitory effects of aminocaproic acid appear to be principally via inhibition of plasminogen activator substances and to a lesser degree, through antiplasmin activity. The drug is absorbed rapidly following oral administration. Whether administered by the oral or i.v. route, a major portion of the compound is recovered unmetabolized in the urine. The renal clearance of aminocaproic acid is high (about 75 % of the creatinine clearance). Thus, the drug is excreted rapidly. After prolonged administration, aminocaproic acid distributes throughout both the extravascular and intravascular compartments of the body and readily penetrates human red blood and other tissue cells.
Indications And Clinical Uses: Aminocaproic acid is useful in enhancing hemostasis when fibrinolysis contributes to bleeding. In life-threatening situations, fresh whole blood transfusions, fibrinogen infusions and other emergency measures may be required.
Fibrinolytic bleeding may frequently be associated with surgical complications following heart surgery (with or without cardiac bypass procedures) and portocaval shunt, hematological disorders such as aplastic anemia, abruptio placentae, hepatic cirrhosis, neoplastic disease such as carcinoma of the prostate, lung, stomach and cervix.
Urinary fibrinolysis, usually a normal physiological phenomenon, may frequently be associated with life-threatening complications following severe trauma, anoxia and shock. Symptomatic of such complications is surgical hematuria (following prostatectomy and nephrectomy) or nonsurgical hematuria (accompanying polycystic or neoplastic diseases of the genitourinary system (see Warnings).
Increased fibrinolytic activity has been demonstrated in the cerebrospinal fluid of patients with proved aneurysmal subarachnoid hemorrhage. Studies indicate a significant reduction in incidence of both death and proven rebleeds when treatment with aminocaproic acid is started within 7 days and continued through 14 days following the initial bleed.
As an inhibitor of plasminogen activation and by impeding the natural process of clot lysis, aminocaproic acid has been shown to be an effective agent as an adjunct in replacement therapy in hemophiliac patients undergoing tooth extractions.
Contra-Indications: Aminocaproic acid should not be used when there is evidence of an active intravascular clotting process.
When there is uncertainty as to whether the cause of bleeding is primary fibrinolysis or disseminated intravascular coagulation (DIC), this distinction must be made before administering aminocaproic acid. The following tests can be applied to differentiate the two conditions: Platelet count is usually decreased in DIC but normal in primary fibrinolysis.
Protamine Paracoagulation test is positive in DIC; a precipitate forms when protamine sulfate is dropped in citrated plasma. The test is negative in the presence of primary fibrinolysis.
The euglobin clot lysis test is abnormal in primary fibrinolysis, but normal in DIC.
Aminocaproic acid must not be used in the presence of DIC without concomitant heparin.
Pregnancy: The effect on the fetus and transplacental passage of this drug is unknown. Therefore, its use during the first and second trimesters should be confined to instances where need outweighs possible hazards.
Manufacturers’ Warnings In Clinical States: The drug is offered for use only in potentially acute life-threatening situations where hemorrhage results from an overactivity of the fibrinolytic system.
Antifertility effects, consistent with the drug’s antifibrinolytic activity, have been suggested in some rodent studies.
In patients with upper urinary tract bleeding, administration of aminocaproic acid has been known to cause intrarenal obstruction in the form of glomerular capillary thrombosis, or clots in the renal pelvis and ureters. For this reason, aminocaproic acid should not be used in hematuria of upper urinary tract origin, unless the possible benefits outweigh the risk.
Precautions: The use of aminocaproic acid should be accompanied by tests designed to determine the amount of fibrinolysis present. There are presently available (a) general tests, such as those for the determination of the lysis of a clot of blood or plasma and (b) more specific tests for the study of various phases of fibrinolytic mechanisms. These latter tests include both semi-quantitative and quantitative techniques for the determination of profibrinolysin, fibrinolysin and anti-fibrinolysin.
Animal experiments indicate particular caution should be taken in administering aminocaproic acid to patients with cardiac, hepatic or renal diseases.
Demonstrable animal pathology in some cases has shown endocardial hemorrhages and myocardial fat degeneration. The use of this drug should thus be restricted to patients in whom the benefit expected would outweigh the hazard.
Rapid i.v. administration of the drug should be avoided since this may induce hypotension, bradycardia and/or arrhythmia.
One case of cardiac and hepatic lesions observed in man has been reported. The patient received 2 g of aminocaproic acid every 6 hours for a total dose of 26 g. Death was due to continued cerebral vascular hemorrhage. Necrotic changes in the heart and liver were noted at autopsy.
Fibrinolysis is a normal process, potentially active at all times to ensure the fluidity of blood. Inhibition of fibrinolysis by aminocaproic acid may result in clotting or thrombosis. However, there is no definite evidence that administration of aminocaproic acid has been responsible for the few reported cases intravascular clotting which followed this treatment. Rather, it appears that such intravascular clotting was most likely due to the patient’s pre-existing clinical condition, e.g., the presence of DIC.
It has been postulated that extravascular clots formed in vivo with incorporated aminocaproic acid may not undergo spontaneous lysis as do normal clots. However, it is the consensus of experts that the few reported cases of extravascular clotting could have occurred in the absence of aminocaproic acid treatment.
Adverse Reactions: Occasionally nausea, cramps, diarrhea, dizziness, tinnitus, malaise, conjunctival suffusion, nasal stuffiness, headache, myopathy and skin rash have been reported as results of the administration of aminocaproic acid. Only rarely has it been necessary to discontinue or reduce medication because of one or more of these effects.
There have also been some reports of dry ejaculation during the period of aminocaproic acid treatment. These have been reported to date only in hemophiliac patients who received the drug after undergoing dental surgical procedures. However, this symptom resolved in all patients within 24 to 48 hours of completion of therapy.
One case of a convulsion occurring, following i.v. administration of aminocaproic acid, has been reported. However, definite association between the seizure and the drug has not been established.
Thrombophlebitis, a possibility with all i.v. therapy, should be guarded against by strict attention to the proper insertion of the needle and the fixing of its position.
Dosage And Administration: Therapy is recommended as follows for all indications other than subarachnoid hemorrhage and dental extractions in hemophiliacs: An initial priming dose of 5 g of aminocaproic acid administered either orally or i.v. followed by 1 to 1.25 g doses at hourly intervals thereafter should achieve and sustain plasma levels of 0.130 mg/mL of the drug. This is the concentration apparently necessary for the inhibition of fibrinolysis. Administration of more than 30 g in any 24-hour period is not recommended.
I.V.: Administer by infusion, utilizing the usual compatible i.v. vehicles (e.g., water for injection, physiologic saline, 5% dextrose or Ringer’s solution). Rapid injection of aminocaproic acid i.v. undiluted into a vein is not recommended.
For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 16 to 20 mL (4 or 5 g) of aminocaproic acid i.v. in 250 mL of diluent be administered by infusion during the first hour of treatment, followed by a continuing infusion at the rate of 4 mL (1 g)/hour in 50 mL of diluent. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled.
Oral Therapy: If the patient is able to take medication by mouth, an identical dosage regimen may be followed by administering the tablets or syrup as follows: For the treatment of acute bleeding syndromes due to elevated fibrinolytic activity, it is suggested that 10 tablets (5 g) or 20 mL of syrup (5 g) of aminocaproic acid be administered during the first hour of treatment, followed by a continuing rate of 2 tablets (1 g) or 5 mL of syrup (1.25g)/hour. This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled.
Therapy for Subarachnoid Hemorrhage: 36 g/day i.v. by continuous infusion, administered as 18 g in 400 mL 5% dextrose every 12 hours for 10 days. Then continue with oral therapy of 3 g every 2 hours until surgery is performed.
If surgery is not performed, antifibrinolytic therapy may be continued for 21 days following the last bleed. Dosage should then be reduced to 24 g/day (2 g every 2 hours) for 3 days, followed by 1 g every 2 hours for 3 days, then discontinued.
Therapy for Hemophiliacs undergoing Dental Extractions: Following preoperative treatment with a loading dose of Factor VIII or IX to raise factor levels to at least 30 to 50%, administer 6 g orally as soon as possible postoperatively, followed by 6 g orally every 6 hours (total dose of 24 g/24 hours) for a 9- to 10-day period.
Availability And Storage: Injectable: Each mL of aqueous solution contains: epsilon aminocaproic acid 250 mg with benzyl alcohol 0.9% as preservative. Vials of 20 mL, packages of 12.
Syrup: Each mL contains: epsilon aminocaproic acid 250 mg. Nonmedicinal ingredients: citric acid, flavor raspberry, hydrochloric acid, potassium sorbate, sodium benzoate, sodium hydroxide, sorbitol solution and water purified. Energy: 50.2 kJ (12.0 kcal)/5 mL.
Tablets: Each round, scored, white tablet, engraved “LL” and “A10”, contains: epsilon aminocaproic acid 500 mg. Energy:
AMICAR® Wyeth-Ayerst Epsilon Aminocaproic Acid Antifibrinolytic Agent