AMINOCAPROIC ACID
DESCRIPTION:
Aminocaproic acid is 6-aminohexanoic acid, which acts as an inhibitor
of fibrinolysis.
AMINOCAPROIC ACID is soluble in water, acid and alkaline solutions; it is sparingly
soluble in methanol and practically insoluble in chloroform.
.
ACTIONS/CLINICAL PHARMACOLOGY:
The fibrinolysis-inhibitory effects of AMINOCAPROIC ACID appear to be exerted principally
via inhibition of plasminogen activators and to a lesser degree through
antiplasmin activity.
In adults, oral absorption appears to be a zero- order process with an
absorption rate of 5.2 g/hr. The mean lag time in absorption is 10 minutes.
After a single oral dose of 5 g, absorption was complete (F=1). Mean +/- SD peak
plasma concentrations (164 +/- 28 mcg/mL) were reached within 1.2 +/- 0.45
hours.
After oral administration, the apparent volume of distribution was estimated to
be 23.1 +/- 6.6 L (mean +/- SD). Correspondingly, the volume of distribution
after intravenous administration has been reported to be 30.0 +/- 8.2 L. After
prolonged administration, AMINOCAPROIC ACID has been found to distribute throughout
extravascular and intravascular compartments of the body, penetrating human red
blood cells as well as other tissue cells.
Renal excretion is the primary route of elimination, whether AMINOCAPROIC ACID is
administered orally or intravenously. Sixty-five percent of the dose is
recovered in the urine as unchanged drug and 11% of the dose appears as the
metabolite adipic acid. Renal clearance (116 mL/min) approximates endogenous
creatinine clearance. The total body clearance is 169 mL/min. The terminal
elimination half-life for AMINOCAPROIC ACID is approximately 2 hours.
INDICATIONS AND USAGE:
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
portacaval 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.)
CONTRAINDICATIONS:
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 into citrated plasma. The test is negative in the
presence of primary fibrinolysis.
* The euglobulin 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.
WARNINGS:
In patients with upper urinary tract bleeding, AMINOCAPROIC ACID administration 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.
Subendocardial hemorrhages have been observed in dogs given intravenous
infusions of 0.2 times the maximum human therapeutic dose of AMINOCAPROIC ACID and in
monkeys given 8 times the maximum human therapeutic dose of AMINOCAPROIC ACID.
Fatty degeneration of the myocardium has been reported in dogs given intravenous
doses of AMINOCAPROIC ACID at 0.8 to 3.3 times the maximum human therapeutic dose and in
monkeys given intravenous doses of AMINOCAPROIC ACID at 6 times the maximum human
therapeutic dose.
Rarely, skeletal muscle weakness with necrosis of muscle fibers has been
reported following prolonged administration. Clinical presentation may range
from mild myalgias with weakness and fatigue to a severe proximal myopathy with
rhabdomyolysis, myoglobinuria, and acute renal failure. Muscle enzymes,
especially creatine phosphokinase (CPK) are elevated. CPK levels should be
monitored in patients on long-term therapy. AMINOCAPROIC ACID administration should be
stopped if a rise in CPK is noted. Resolution follows discontinuation of AMINOCAPROIC ACID;
however, the syndrome may recur if AMINOCAPROIC ACID is restarted.
The possibility of cardiac muscle damage should also be considered when skeletal
myopathy occurs. 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 cerebrovascular hemorrhage.
Necrotic changes in the heart and liver were noted at autopsy.
PRECAUTIONS:
GENERAL
AMINOCAPROIC ACID Injection contains benzyl alcohol as a preservative and is not
recommended for use in newborns.
AMINOCAPROIC ACID inhibits both the action of plasminogen activators and to a lesser
degree, plasmin activity. The drug should NOT be administered without a definite
diagnosis and/or laboratory finding indicative of hyperfibrinolysis
(hyperplasminemia).(REF. 1)
Rapid intravenous administration of the drug should be avoided since this may
induce hypotension, bradycardia, and/or arrhythmia.
Inhibition of fibrinolysis by aminocaproic acid may theoretically result in
clotting or thrombosis. However, there is no definite evidence that
administration of aminocaproic acid has been responsible for the few reported
cases of intravascular clotting which followed this treatment. Rather, it
appears that such intravascular clotting was most likely due to the patient's
preexisting clinical condition, e.g., the presence of DIC. It has been
postulated that extravascular clots formed IN VIVO may not undergo spontaneous
lysis as do normal clots.
Reports have appeared in the literature of an increased incidence of certain
neurological deficits such as hydrocephalus, cerebral ischemia, or cerebral
vasospasm associated with the use of antifibrinolytic agents in the treatment of
subarachnoid hemorrhage (SAH). All of these events have also been described as
part of the natural course of SAH, or as a consequence of diagnostic procedures
such as angiography. Drug relatedness remains unclear.
Thrombophlebitis, a possibility with all intravenous therapy, should be guarded
against by strict attention to the proper insertion of the needle and the fixing
of its position.
Thrombosis with severe sequelae (acute myocardial infarction, gangrene) has been
rarely reported in patients with hemophilia receiving combined treatment with
Factor IX concentrate and AMINOCAPROIC ACID. AMINOCAPROIC ACID should not be administered
concomitantly with prothrombin complex concentrates or with activated
prothrombin concentrates unless the increased risk of thrombosis is outweighed
by the anticipated clinical benefit.
LABORATORY TESTS
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 semiquantitative and
quantitative techniques for the determination of profibrinolysin, fibrinolysin,
and antifibrinolysin.
DRUG LABORATORY TEST INTERACTIONS
Prolongation of the template bleeding time has been reported during continuous
intravenous infusion of AMINOCAPROIC ACID at dosages exceeding 24 g/day. Platelet function
studies in these patients have not demonstrated any significant platelet
dysfunction. However, In Vitro studies have shown that at high concentrations
(7.4 mMol/L or 0.97 mg/mL and greater) EACA inhibits ADP and collagen-induced
platelet aggregation, the release of ATP and serotonin, and the binding of
fibrinogen to the platelets in a concentration- response manner. Following a 10
g bolus of AMINOCAPROIC ACID, transient peak plasma concentrations of 4.6 mMol/L or 0.60
mg/mL have been obtained. The concentration of AMINOCAPROIC ACID necessary to maintain
inhibition of fibrinolysis is 0.99 mMol/L or 0.13mg/mL. Administration of a 5 g
bolus followed by 1 to 1.25 g/hr should achieve and sustain plasma levels of
0.13 mg/mL. Thus, concentrations which have been obtained IN VIVO clinically in
patients with normal renal function are considerably lower than the In Vitro
concentrations found to induce abnormalities in platelet function tests.
However, higher plasma concentrations of AMINOCAPROIC ACID may occur in patients with
severe renal failure.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Long-term studies in animals to evaluate the carcinogenic potential of AMINOCAPROIC ACID
and studies to evaluate its mutagenic potential have not been conducted. Dietary
administration of an equivalent of the maximum human therapeutic dose of AMINOCAPROIC ACID
to rats of both sexes impaired fertility as evidenced by decreased
implantations, litter sizes and number of pups born.
PREGNANCY
PREGNANCY CATEGORY C. Animal teratological studies have not been conducted with
AMINOCAPROIC ACID. It is also not known whether AMINOCAPROIC ACID can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. AMINOCAPROIC ACID
should be given to a pregnant woman only if clearly needed.
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 AMINOCAPROIC ACID is
administered to a nursing woman.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS:
AMINOCAPROIC ACID is generally well tolerated. The following adverse experiences have been
reported:
General: Edema, fever, headache, hemorrhage, malaise.
Hypersensitivity Reactions: Allergic and anaphylactoid reactions, anaphylaxis.
Local Reactions: Injection site reactions, pain and necrosis.
Cardiovascular: Bradycardia, hypotension, ischemia, thrombosis.
Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting.
Hematologic: Agranulocytosis, coagulation disorder, leukopenia,
thrombocytopenia.
Musculoskeletal: CPK increased, muscle weakness, myalgia, myopathy (see
WARNINGS), myositis, rhabdomyolysis.
Neurologic: Confusion, convulsions, delirium, dizziness, hallucinations,
intracranial hypertension, stroke, syncope.
Respiratory: Dyspnea, nasal congestion, pulmonary embolism.
Skin: Pruritus, rash.
Special Senses: Deafness, glaucoma, tinnitus, vision decreased, watery eyes.
Urogenital: BUN increased, ejaculatory disorder, renal failure.
OVERDOSAGE:
A few cases of acute overdosage with AMINOCAPROIC ACID administered intravenously have been
reported. The effects have ranged from no reaction to transient hypotension to
severe acute renal failure leading to death. One patient with a history of brain
tumor and seizures experienced seizures after receiving an 8 gram bolus
injection of AMINOCAPROIC ACID. The single dose of AMINOCAPROIC ACID causing symptoms of overdosage or
considered to be life-threatening is unknown. Patients have tolerated doses as
high as 100 grams while acute renal failure has been reported following a dose
of 12 grams.
The intravenous and oral LD50 of AMINOCAPROIC ACID were 3.0 and 12.0 g/kg, respectively, in
the mouse and 3.2 and 16.4 g/kg, respectively, in the rat. An intravenous
infusion dose of 2.3 g/kg was lethal in the dog. On intravenous administration,
tonic- clonic convulsions were observed in dogs and mice.
No treatment for overdosage is known, although evidence exists that AMINOCAPROIC ACID is
removed by hemodialysis and may be removed by peritoneal dialysis.
Pharmacokinetic studies have shown that total body clearance of AMINOCAPROIC ACID is
markedly decreased in patients with severe renal failure.
DOSAGE AND ADMINISTRATION:
INTRAVENOUS
AMINOCAPROIC ACID (aminocaproic acid) Injection is administered by infusion, utilizing the
usual compatible intravenous vehicles (e.g., Sterile Water for Injection, Sodium
Chloride for Injection, 5% Dextrose or Ringer's Injection). Although Sterile
Water for Injection is compatible for intravenous injection the resultant
solution is hypo-osmolar. RAPID INJECTION OF AMINOCAPROIC ACID INJECTION 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 to 5 g) of AMINOCAPROIC ACID Injection 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) per 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.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
ORAL THERAPY
If the patient is able to take medication by mouth, an identical dosage regimen
may be followed by administering AMINOCAPROIC ACID Tablets or AMINOCAPROIC ACID Syrup, 25% as follows:
For the treatment of acute bleeding syndromes due to elevated fibrinolytic
activity, it is suggested that 10 tablets (5 g) or 4 teaspoonfuls 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 1 teaspoonful of syrup (1.25 g) per hour.
This method of treatment would ordinarily be continued for about 8 hours or
until the bleeding situation has been controlled.
REFERENCES:
1. Stefanini M, Dameshek W: The Hemorrhagic Disorders, Ed. 2, New York, Grune
and Stratton. 1962; pp. 510-514.
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