Aminocaproic Acid (Systemic)



JAN:

Epsilon-aminocaproic acid {05}

VA CLASSIFICATION
Primary: BL116

Commonly used brand name(s): Amicar.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antifibrinolytic—

antihemorrhagic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hemorrhage, hyperfibrinolysis-induced (treatment)
Hemorrhage, postsurgical (prophylaxis and treatment)
[Hemorrhage, oral, in patients with hemophilia (treatment) ] or
[Hemorrhage, following dental and oral surgery, in patients with hemophilia (prophylaxis and treatment)]—Aminocaproic acid is indicated for treatment of severe bleeding that may occur following heart surgery (with or without cardiac bypass procedures) and portacaval shunt, prostatectomy, or nephrectomy, and in association with hematologic disorders (such as aplastic anemia), abruptio placentae (with laboratory confirmation of hyperfibrinolysis), hepatic cirrhosis, neoplastic disease, and polycystic or neoplastic diseases of the genitourinary system {01} {02} {06} {10}{21}.
—[Aminocaproic acid is used in the management of hemophilic patients (i.e., patients with Factor VIII or Factor IX deficiency ) who have oral mucosal bleeding, or are undergoing oral surgery, including tooth extractions or other dental surgical procedures. The medication prevents or decreases hemorrhaging in these patients and reduces the need for administration of clotting factors, particularly when desmopressin is also used {18} {19} {20} .]
—[Aminocaproic acid is also used to prevent intra- and postoperative hemorrhaging in patients with clotting defects other than hemophilia (including von Willebrand disease or deficiencies of factors other than Factor VIII or Factor IX).]1
—[Aminocaproic acid is used to treat severe hemorrhaging caused by thrombolytic agents (alteplase [tissue-type plasminogen activator, recombinant], anistreplase [anisoylated plasminogen-streptokinase activator complex], streptokinase, or urokinase). However, controlled studies to demonstrate its efficacy for this use have not been done in humans. {03}]1

[Hemorrhage, subarachnoid, recurrence (prophylaxis) ]—Aminocaproic acid is used to prevent recurrence of subarachnoid hemorrhage, especially when surgery is delayed {06}.

Note: In some patients receiving treatment for hemorrhaging, other emergency measures including transfusion of whole blood, fresh frozen plasma, specific clotting factors, or fibrinogen may be needed.
Aminocaproic acid is ineffective in bleeding caused by loss of vascular integrity; a definite clinical diagnosis or laboratory findings indicative of hyperfibrinolysis (hyperplasminemia) is essential prior to initiation of aminocaproic acid therapy. However, some conditions and laboratory findings suggestive of hyperfibrinolysis are also present in disseminated intravascular coagulation; differentiation between the two conditions is essential because aminocaproic acid may promote thrombus formation in patients with disseminated intravascular coagulation and must not be used unless heparin is administered concurrently. The following criteria may be useful in differential diagnosis: {01} {02} {06} {10}

Test
Primary
Hyperfibrinolysis
Results
Disseminated
Intravascular
Coagulation
Results
Platelet count *
Normal
Decreased
Protamine para-
coagulation test
Negative
Positive
Euglobulin clot
lysis time
Decreased
Normal
* Following extracorporeal circulation (during cardiovascular surgery), decreased platelet count may not be useful for differentiating between primary hyperfibrinolysis and disseminated intravascular coagulation; the other criteria may be more useful in differential diagnosis in these patients.


1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    131.17 {05} {10}

Mechanism of action/Effect:

Aminocaproic acid competitively inhibits activation of plasminogen {01} {02} {06} {10}, thereby reducing conversion of plasminogen to plasmin (fibrinolysin), an enzyme that degrades fibrin clots as well as fibrinogen and other plasma proteins including the procoagulant factors V and VIII {16} {17}. Aminocaproic acid also directly inhibits plasmin activity, but higher doses are required than are needed to reduce plasmin formation {01} {02}. In vitro , the antifibrinolytic potency of aminocaproic acid is approximately one-fifth to one-tenth that of tranexamic acid {04}.

Absorption:

Absorbed rapidly following oral administration {01} {06}{21}.

Protein binding:

Does not appear to bind to plasma protein.

Half-life:


Elimination:

Terminal, 2 hours . {21}


Time to peak concentration:

Within 2 hours following a single oral dose.

Therapeutic plasma concentration

For inhibition of systemic hyperfibrinolysis—130 mcg per mL (991 micromoles/L) {01} {10}.

For prevention of recurrent subarachnoid hemorrhage—150 to 300 mcg per mL (1143 to 2287 micromoles/L) {11} {12}.

Elimination:
    Renal. Excreted rapidly {06}, mostly as unchanged drug {01} {10}.


Precautions to Consider

Pregnancy/Reproduction
Fertility—
Studies in rodents have suggested an adverse effect on fertility, consistent with aminocaproic acid"s antifibrinolytic activity {01} {06}.

Pregnancy—
Studies have not been done in humans {10}.

Studies have not been done in animals {10}.

Note: When aminocaproic acid is used topically as an oral rinse to control gingival bleeding in hemophilic patients during the first and second trimesters of pregnancy, the patient should be instructed not to swallow the syrup {22}.


FDA Pregnancy Category C {10}{21}.

Breast-feeding

It is not known whether aminocaproic acid is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Although studies on the relationship of age to the effects of aminocaproic acid have not been performed in the pediatric population, no pediatrics-specific problems attributed to aminocaproic acid have been documented to date. However, aminocaproic acid injections that contain benzyl alcohol should not be administered to premature neonates because the preservative has been associated with a fatal toxic syndrome consisting of metabolic acidosis, central nervous system (CNS) depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages in these patients.


Geriatrics


Although studies on the relationship of age to the effects of aminocaproic acid have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may require dosage reduction in patients receiving aminocaproic acid.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anti-inhibitor coagulant complex or
Factor IX complex    (although aminocaproic acid is often used in conjunction with clotting factor replacement for the perisurgical management of hemophilic patients, concurrent use may increase the risk of thrombotic complications {07} {13} {14} {15}{21}; using aminocaproic acid as an oral rinse for oral surgical procedures and tooth extractions may minimize this complication {18}; some hematologists recommend that administration of aminocaproic acid be delayed for 8 hours following injection of either of the clotting factor complexes {07})


Contraceptives, estrogen-containing, oral or
Estrogens    (concurrent use with aminocaproic acid may increase the potential for thrombus formation)


Thrombolytic agents    (the actions of aminocaproic acid and of thrombolytic agents [e.g., alteplase (tissue-type plasminogen activator, recombinant; tPA), anistreplase (anisoylated plasminogen-streptokinase activator complex; APSAC), streptokinase, or urokinase] are mutually antagonistic; although controlled studies to demonstrate its efficacy for this use have not been done in humans, aminocaproic acid may be useful in treating severe hemorrhage caused by a thrombolytic agent {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Intravascular clotting, active {06} {10}{21}    (risk of serious, even fatal, thrombus formation)


Risk-benefit should be considered when the following medical problems exist
Cardiac disease {06}    (aminocaproic acid may cause hypotension and bradycardia, especially with rapid intravenous administration or if the patient is hypovolemic; also, endocardial hemorrhages and myocardial fat degeneration have been demonstrated in animals )


Hematuria of upper urinary tract origin {06} {10}{21}    (risk of intrarenal obstruction secondary to clot retention in the renal pelvis and ureters)


Hepatic disease {06}    (cause of bleeding may be more difficult to diagnose)


Renal disease {06}    (medication may accumulate; reduction in dosage may be required; also, aminocaproic acid has caused acute renal failure in a few patients and kidney concretions in animals)


Sensitivity to aminocaproic acid
Thrombosis, predisposition to, or history of    (medication inhibits clot dissolution and may interfere with mechanisms for maintaining blood vessel patency)




Side/Adverse Effects

Note: Patients receiving this medication must be monitored for signs of thromboembolic complications.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Bladder obstruction caused by blood clot formation (decreased urination)
    
decrease in blood pressure {06} {09} — may reach hypotensive levels
    
dizziness {06} {10}
    
headache {06}
    
myopathy {06}{21} ( muscular pain or weakness, severe and continuing)—may be associated with necrosis of muscle fibers
    
renal failure ( sudden decrease in amount of urine; swelling of face, fingers, feet, or lower legs; rapid weight gain)
    
ringing or buzzing in ears {06}{21}
    
skin rash {06} {10}
    
slow or irregular heartbeat —after too-rapid intravenous administration
    
stomach cramps
    
stuffy nose {06} {10}
    
thrombosis or thromboembolism {06} (pains in chest, groin, or legs [especially calves] ; severe, sudden headache; sudden and unexplained shortness of breath, slurred speech, vision changes, and/or weakness or numbness in arm or leg; sudden loss of coordination)—signs and symptoms depend on site of thrombus formation or embolization
    
unusual tiredness or weakness {06} {10} — after too-rapid intravenous administration

Incidence rare
    
Rhabdomyolysis with myoglobinuria and renal failure {06} {09} {10}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Diarrhea {06}
    
dry ejaculation {06} {09} {10}{21} — reported in hemophilia patients receiving the medication in conjunction with dental surgery; symptom has resolved within 24 to 48 hours after cessation of treatment in all cases reported to date
    
nausea or vomiting {06} {10} {21}
    
unusual menstrual discomfort {06} {10} —caused by clotting of menstrual fluid
    
unusual tiredness —with long-term use
    
watery eyes {21}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antifibrinolytic Agents (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to aminocaproic acid
Other medical problems, especially active intravascular clotting

Proper use of this medication
» Importance of not using more or less medication than the amount prescribed

» Proper dosing
Missed dose: Taking as soon as possible, then returning to regular dosing schedule or doubling next dose

» Proper storage


Side/adverse effects
Signs and symptoms of potential side effects, especially bladder obstruction caused by blood clot formation, decrease in blood pressure, dizziness, headache, myopathy, renal failure, ringing or buzzing in ears, skin rash, slow or irregular heartbeat, stomach cramps, stuffy nose, thrombosis or thromboembolism, unusual tiredness or weakness, and rhabdomyolysis with myoglobinuria and renal failure


General Dosing Information
When aminocaproic acid is used during surgery, the bladder must first be freed of clots. Aminocaproic acid may accumulate in the clots and inhibit their dissolution.

A reduction in dosage may be required in patients with renal function impairment.

Aminocaproic acid therapy may be discontinued when there is evidence of cessation of bleeding or when laboratory determinations of fibrinolysis indicate that the medication is no longer required.

Aminocaproic acid syrup may be given as an oral rinse for the control of bleeding during dental and oral surgery in hemophilic patients {18} {22}.

For parenteral dosage forms only
Intravenous injection of the undiluted aminocaproic acid solution is not recommended {06}.

Rapid intravenous administration may induce hypotension or bradycardia and should be avoided {06} {10}.

To help minimize the possibility of thrombophlebitis, careful attention to the proper insertion of the needle and the fixing of its position is necessary before administration of this medication {06}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

AMINOCAPROIC ACID SYRUP USP

Usual adult dose
Acute bleeding syndromes
Oral, 5 grams the first hour, followed by 1 or 1.25 grams per hour for approximately eight hours or until the desired response is obtained {06} {10} {21}.

Note: Following prostatic surgery, a lower dose of 6 grams in the first twenty-four hours may be sufficient, since aminocaproic acid is concentrated in the urine. Also, the lower dosage may reduce the risk of clot formation and subsequent obstruction in the bladder. {08}


[Prevention and treatment of oral hemorrhage, including hemorrhage following dental surgery, in hemophilic patients]
Oral, 75 mg per kg of body weight (up to 6 grams) immediately following surgery, then every six hours for seven to ten days {18} {19} {23}.
Oral rinse, 5 mL (1.25 grams) swished for thirty seconds four times a day for seven to ten days; small quantities may be swallowed, except when used during the first and second trimesters of pregnancy. In children or unconscious patients, the syrup may be applied with an applicator. {18} {22}

Note:  When aminocaproic acid is used, a single factor VIII infusion of 40 International Units per kg of body weight, or coagulation factor IX infusion of 60 International Units per kg of body weight prior to surgery is often enough for normal hemostasis {24} {25}. However, because of an increased risk of thrombotic complications when aminocaproic acid and Factor IX or anti-inhibitor coagulant complex are administered concurrently, some hematologists recommend that aminocaproic acid not be administered within eight hours of these clotting factor concentrates.


[Hemorrhage, subarachnoid, recurrence]
To be administered following initial intravenous therapy: Oral, 36 grams per day (3 grams every two hours) until surgery is performed. If surgery is not performed, continue therapy with 3 grams every two hours for twenty-one days after the last bleeding episode. Dosage should then be reduced to 24 grams per day (2 grams every two hours) for three days, then to 12 grams per day (1 gram every two hours) for three days, prior to discontinuation of the medication. {02} {06}


Usual adult prescribing limits
[Hemorrhage, subarachnoid, recurrence]—36 grams per twenty-four hours {06}.

Other indications—Up to 24 grams per twenty-four hours {23}.

Usual pediatric dose
Acute bleeding syndromes
Oral, 100 mg per kg of body weight or 3 grams per square meter of body surface the first hour, followed by 33.3 mg per kg of body weight or 1 gram per square meter of body surface per hour, not to exceed 18 grams per square meter of body surface in twenty-four hours.

[Prevention and treatment of oral hemorrhage, including hemorrhage following dental surgery, in hemophilic patients]
See Usual adult dose .


Strength(s) usually available
U.S.—


250 mg per mL (1.25 grams per 5 mL) (Rx) [Amicar ( methylparaben, 0.2%) (propylparaben, 0.05%) (edetate disodium, 0.3%) (citric acid ) (flavorings) (sodium saccharin) (sorbitol)]

Canada—


250 mg per mL (1.25 grams per 5 mL) (Rx) [Amicar (potassium sorbate 0.2%) (sodium benzoate 0.1%)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing. {10}


AMINOCAPROIC ACID TABLETS USP

Usual adult dose
See Aminocaproic Acid Syrup USP .

Usual adult prescribing limits
See Aminocaproic Acid Syrup USP .

Usual pediatric dose
See Aminocaproic Acid Syrup USP .

Strength(s) usually available
U.S.—


500 mg (Rx) [Amicar (magnesium stearate) ( stearic acid) (povidone)]

Canada—


500 mg (Rx) [Amicar]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. {10}



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

AMINOCAPROIC ACID INJECTION USP

Usual adult dose
Acute bleeding syndromes
Intravenous infusion, initially 4 to 5 grams administered over a period of one hour, followed by continuous infusion at the rate of 1 gram per hour for approximately eight hours or until the desired response is obtained {06}{10} {21}.

Note: Following prostatic surgery, a lower dose of 6 grams in the first twenty-four hours may be sufficient, since aminocaproic acid is concentrated in the urine. Also, the lower dosage may reduce the risk of clot formation and subsequent obstruction in the bladder.


[Prevention and treatment of oral hemorrhage, including hemorrhage following dental surgery, in hemophilic patients]
Intravenous infusion, 75 mg per kg of body weight (up to 6 grams) immediately following surgery, then every six hours for seven to ten days {18} {19} {23}.

Note: When aminocaproic acid is used, a single factor VIII infusion of 40 International Units per kg of body weight or coagulation factor IX infusion of 60 International Units per kg of body weight prior to surgery is often enough for normal hemostasis {24} {25}. However, because of an increased risk of thrombotic complications when aminocaproic acid and Factor IX or anti-inhibitor coagulant complex are administered concurrently, some hematologists recommend that aminocaproic acid not be administered within eight hours of these clotting factor concentrates.


[Hemorrhage, subarachnoid, recurrence]
Intravenous infusion, 36 grams per day (18 grams in 400 mL of 5% dextrose injection infused over each twelve-hour period) for ten days. Therapy is continued using orally administered aminocaproic acid. {02} {06}


Usual adult prescribing limits
[Hemorrhage, subarachnoid, recurrence]—36 grams per twenty-four hours.

Other indications—Up to 24 grams per twenty-four hours {23}.

Usual pediatric dose
Acute bleeding syndromes
Intravenous infusion, initially 100 mg per kg of body weight or 3 grams per square meter of body surface over a period of one hour, followed by continuous infusion at the rate of 33.3 mg per kg of body weight or 1 gram per square meter of body surface per hour, not to exceed 18 grams per square meter of body surface in twenty-four hours.

[Prevention and treatment of oral hemorrhage, including hemorrhage following dental surgery, in hemophilic patients]
See Usual adult dose .


Strength(s) usually available
U.S.—


250 mg per mL (Rx) [Amicar (benzyl alcohol)][Generic](may contain benzyl alcohol—see labeling for individual product)

Canada—


250 mg per mL (Rx) [Amicar (benzyl alcohol)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing. {10}

Preparation of dosage form:
For administration by slow intravenous infusion, the 250-mg-per-mL concentration must be diluted with a compatible intravenous vehicle such as sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer"s injection. Although sterile water for injection is compatible for intravenous injection, the resultant solution is hypo–osmolar{06} {10}{21}. Dilution with sterile water for injection is not recommended when the medication is used in patients with subarachnoid hemorrhage.



Revised: 09/23/1999



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. PDR Physicians" desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company; 1988. p. 1133.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 22nd ed. Ottawa: Canadian Pharmaceutical Association; 1987. p. 27.
  1. Marder VJ. Comparison of thrombolytic agents: selected hematologic, vascular and clinical events. Am J Cardiol 1989; 64: 2A-7A.
  1. Cyklokapron package insert (KabiVitrum—US), Rev 1/87, Rec 6/87.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1993. p. 42.
  1. Amicar package insert (Lederle—Canada), Rev 4/89, Rec 6/30/93.
  1. AMA Drug evaluations. 6th ed. Chicago: American Medical Association, September 1986: 648.
  1. Panel comment.
  1. PDR Physicians" desk reference. 45th ed. 1991. Oradell, NJ: Medical Economics Data; 1991. p. 1165-6.
  1. Amicar (Immunex). In: PDR Physicians" desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data; 1994. p. 1063-4.
  1. Reviewer comment, 9/91.
  1. Heras RC. Preoperative management of the patient with a ruptured intracranial aneurysm. Semin Neurology 1984; 4: 430-8.
  1. Konyne 80 package insert (Cutter—US), Rev 4/91, Rec 4/12/93.
  1. Agrawal BL, Zelkowitz L, Hletko P. Acute myocardial infarction in a young hemophiliac patient during therapy with factor IX concentrate and epsilon aminocaproic acid. J Pediatr 1981; 98: 931-3.
  1. Wyngaarden JB, Smith LH, editors. Cecil textbook of medicine. 18th ed. Philadelphia: WB Saunders; 1988. p. 1071-2.
  1. Ferres H. Preclinical pharmacological evaluation of anisoylated plasminogen streptokinase activator complex. Drugs 1987; 33(Suppl 3): 33-50.
  1. Fears R. Development of anisoylated plasminogen-streptokinase activator complex from the acyl enzyme concept. Semin Thromb Hemost 1989; 15: 129-39.
  1. Association of Hemophilia Clinic Directors of Canada. Hemophilia and von Willebrand"s disease: 2. Management. Can Med Assoc J 1995; 153: 147-57.
  1. Panel comment per Hemophilia monograph reviewed 1/97.
  1. Panel comment per Hemophilia monograph reviewed 3/97.
  1. Product Information: Amicar ®, aminocaproic acid. Immunex Corporation, Seattle, WA, USA, 1998.
  1. Casdorph DL. Topical aminocaproic acid in hemophilic patients undergoing dental extraction. DICP 1990; 24: 160-1.
  1. Reviewers" consensus on Hemophilia monograph developed 5/97.
  1. Brettler DB, Levine PH. Clinical manifestations and therapy of inherited coagulation factor deficiencies. In: Colman RW, Hirsch J, Marder VJ, et al., editors. Hemostasis and thrombosis: basic principles and clinical practice. 3rd ed. Philadelphia: JB Lippincott; 1994. p. 169-83.
  1. Djulbegovic B, Goldsmith GH. Guidelines for management of hemophilia A and B [letter]. Blood 1995; 85: 598.
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