Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/443
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Aminocaproic Acid (Injection, Solution)
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Intravenous Aminocaproic
Acid Injection, USP 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 suggestedthat 16 to 20 mL (4 to 5 g) of aminocaproic acid 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. Do not administer
unless the solution is clear and seal is intact. Discard unused portion.
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Aminocaproic Acid Injection, USP is a 6-aminohexanoic acid,
which acts as an inhibitor of fibrinolysis and is a white to pale yellow powder
soluble in water. Aminocaproic Acid is soluble in water,
acid and alkaline solutions; it is sparingly soluble in methanol and practically
insoluble in chloroform. Aminocaproic Acid Injection,
USP, for intravenous administration, is a sterile pyrogen-free solution containing
250 mg/mL of aminocaproic acid and Water for Injection. The solution contains
no bacteriostat or antimicrobial agent and is intended for use only as a single-dose
injection. When smaller doses are requiredthe unused portion should be discarded.
Hydrochloric acid may be added to adjust pH to approximately 6.8 during manufacture. Its
chemical structure is: The semi-rigid vial is fabricated from a specifically formulated
polyolefin. It is a copolymer of ethylene and propylene. The safety of the
plastic has been confirmed by tests in animals according to USP biological
standards for plastic containers. The container requires no vapor barrier
to maintain the proper drug concentration.
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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��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.
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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 Injection. The
following tests can be applied to differentiate the two conditions: Aminocaproic Acid Injection must not be used in the presence
of DIC without concomitant heparin.
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Aminocaproic Acid Injection, USP is supplied in single-dose
containers as follows: 5 g/20 mL (250 mg/mL) aminocaproic
acid, 20 mL in 30 mL Fliptop Vial (List No. 4346). Store at 20 to 25��C (68 to 77��F). [See USP Controlled Room Temperature.]
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General: Aminocaproic Acid Injection, 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).* 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 pre-existing 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. Epsilon-aminocaproic
acid should not be administered with Factor IX Complex concentrates or Anti-Inhibitor
Coagulant concentrates, as the risk of thrombosis may be increased.<br/>Laboratory Tests: The use of Aminocaproic Acid Injection, USP 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.<br/>Drug Laboratory Test Interactions: Prolongation of the template bleeding time has been reported
during continuous intravenous infusion of Aminocaproic Acid Injection 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) aminocaproic acid 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 Injection, 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 0.13
mg/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 inpatients with severe renal failure.<br/>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.<br/>Pregnancy: Pregnancy Category C. Animal
reproduction 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
Injection should be given to a pregnant woman only if clearly needed.<br/>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.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not been
established.
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A few cases of acute overdosage with Aminocaproic Acid Injection
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 Injection.
The single dose of Aminocaproic Acid Injection 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 LDof
aminocaproic acid were 3 and 12 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.
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Aminocaproic Acid
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Aminocaproic Acid (Injection, Solution)
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Aminocaproic Acid Injection is generally well tolerated.
The following adverse experiences have been reported: General:
Edema, headache, malaise. Hypersensitivity Reactions:
Allergic and anaphylactoid reactions, anaphylaxis. Local
Reactions: Injection site reactions, pain and necrosis. Cardiovascular:
Bradycardia, hypotension, peripheral 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: Tinnitus, vision decreased, watery
eyes. Urogenital: BUN increased, renal failure. There
have been some reports of dry ejaculation during the period of Aminocaproic
Acid Injection treatment. These have been reported to date only in hemophilia
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.
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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 Injection, USP 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 Injection administration should be
stopped if a rise in CPK is noted. Resolution follows discontinuation of Aminocaproic
Acid Injection; however, the syndrome may recur if Aminocaproic Acid Injection
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.
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Aminocaproic Acid Injection, is useful in enhancing hemostasis
when fibrinolysis contributes to bleeding. In life-threatening situations,
transfusion of appropriate blood products 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 amegakaryocytic thrombocytopenia (accompanying aplastic anemia); acute
and life-threatening abruptio placentae; hepatic cirrhosis; and neoplastic
disease such as carcinoma of the prostate, lung, stomach, and cervix. Urinary
fibrinolysis, usually a normal physiological phenomenon, may contribute to
excessive urinary tract fibrinolytic bleeding associated with surgical hematuria
(following prostatectomy and nephrectomy) or nonsurgical hematuria (accompanying
polycystic or neoplastic diseases of the genitourinary system). (See WARNINGS.)
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Aminocaproic Acid
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