Drug Criteria & Outcomes-A review of tranexamic acid (Cyklokapron)
By Karen Birmingham, PharmD
Pharmacy Practice Resident
Medical University of South Carolina, Charleston
Indications
Tranexamic acid, manufactured by Pharmacia and Upjohn, is indicated for the prevention or reduction of bleeding and reduction of requirement for replacement therapy in hemophiliac patients who are undergoing tooth extraction. It is to be used only for a period of two to eight days.1
Pharmacology
Tranexamic acid is an antifibrinolytic agent synthetically derived from the amino acid lysine. During fibrinolysis, plasminogen adheres to lysine receptors on the surface of the fibrin molecule and is subsequently converted to plasmin by tissue plasminogen activator. Plasmin splits fibrin into large constituents, which are further degraded into more soluble components. A balance in the fibrinolytic system is maintained by the formation of a complex between plasminogen and fibrin and the resulting activation of plasminogen. If there is an excess of soluble fibrin, increased hemorrhage occurs.2
Tranexamic acid maintains the stability of fibrin clots by adhering to lysine binding sites and competitively inhibiting the activation of plasminogen, which prevents the formation of plasmin. At high concentrations, the drug noncompetitively inhibits existing plasmin.1,3-4 In vitro studies have demonstrated that the potency of tranexamic acid is up to 10 times greater than that of aminocaproic acid, another lysine derivative.1,3 Additionally, bond strength to fibrin surface receptors is greater for tranexamic acid than aminocaproic acid. In normal individuals, tranexamic acid prolongs thrombin time, but not coagulation time. Platelet counts and serum blood factor concentrations are unaffected by the drug.1
Pharmacokinetics
When taken orally, approximately 30% to 50% of tranexamic acid is absorbed from the gastrointestinal tract. Food intake does not appear to alter bioavailability. Peak plasma concentration is achieved approximately three hours after oral administration.1 The drug is considered therapeutic at a plasma concentration of 10 mcg/mL, and therapeutic concentrations may remain for seven to 17 hours, depending on the tissue in which the drug is monitored.3
The volume of distribution of tranexamic acid ranges from 9 to 12 liters.1 Less than 3% is bound to plasma protein (i.e., plasminogen). There is no binding to serum albumin.1,3,5 Tranexamic acid diffuses across the blood-brain barrier.2 In certain tissues, such as cerebrospinal fluid and aqueous humor, tranexamic acid concentrations are much lower than in serum. Joint fluid concentrations are equal to serum concentrations.5 The drug is primarily filtered by the glomerulus, and the renal clearance rate mimics the plasma clearance rate of greater than 110 mL/min.1,5 Urinary excretion of an oral dose and an intravenous dose 24 hours after administration is 40% and 90%, respectively. More than 95% of a dose is eliminated as unchanged drug.1
Selected clinical trials
The effect of tranexamic acid on hemorrhage associated with tooth extraction was investigated in patients with hemophilia A (classic hemophilia, n = 20) or hemophilia B (Christmas disease, n = 8).6 The purpose of the trial was to determine if tranexamic acid reduces blood loss and the requirement for replacement therapy with plasma products in patients undergoing tooth extraction. Participants ranged in age from 13 to 65. Subjects who had hematuria at enrollment or within one month prior to enrollment were excluded from the trial. Two hours before the tooth extraction procedure, patients were given either a 1 g oral dose of drug or placebo. Factor VIII or IX was administered one hour prior to surgery. All patients were treated with 1,000 mg of tetracycline per day, divided into four doses. Patients received either placebo or tranexamic acid at a dose of 1 g three times a day for five days. Fecal and oral blood loss were measured daily. If excess bleeding occurred, appropriate replacement therapy was administered. Laboratory tests included quantitation of factors VIII and IX, fibrinolysis assay, hematological indices, assessment of renal and liver function, and 12-lead electrocardiograms.6
The investigators reported a statistically significant decrease in blood loss in the treatment group (p < 0.025). Blood factor replacement was necessary in two patients in the treatment group, while 11 patients required transfusions in the placebo group. The authors failed to comment on the statistical significance of this finding. Both plasma fibrinogen and erythrocyte sedimentation rate were significantly increased in the control group on the last day of treatment (p < 0.05). Fibrinolysis was significantly decreased by tranexamic acid (p < 0.05). There were no differences in renal or liver function or electrocardiograms in either group, nor were any adverse events reported. Blood urea was significantly increased in both groups due to dental surgery (p < 0.05). The investigators concluded that tranexamic acid therapy during and after dental extraction reduces blood loss and requirement for blood factor transfusion in patients with either hemophilia A or B.6
The effect of tranexamic acid treatment on postoperative bleeding and need for replacement therapy was evaluated in patients with hemophilia who were undergoing oral surgery.7 They compared three groups of individuals. The first group (group A) consisted of 17 patients, who received preoperative and postoperative replacement therapy as well as substitution therapy for bleeding with factor VIII/IX:C. In addition, tranexamic acid was administered in doses of 37-123 mg/kg of body weight daily.
Treatment duration varied from three to six days. Four patients in group A were given prophylactic antibiotics. Group B included 14 patients who received factor VIII/IX:C preoperatively and postoperatively, in addition to tranexamic acid at doses of 45-105 mg/kg of body weight. No substitution therapy was administered for hemorrhage. Treatment was continued for six to eight days. These patients also performed oral rinses with 10 mL of a tranexamic acid 5% mouthwash four times a day. This regimen was continued for five to seven days. Six patients in group B received antibiotic prophylaxis. Group C consisted of 11 patients. Replacement therapy was given to patients who demonstrated spontaneous factor VIII/IX:C activity that was less than 10% of the normal activity. Other patients received no substitution therapy but were treated with higher doses of tranexamic acid (72 to 106 mg/kg of body weight). Tranexamic acid 5% mouthwash was administered to all patients four times a day. Treatment duration for systemic therapy and oral rinses were six days and five days, respectively. Antibiotic prophylaxis was administered to 10 patients in group C.7
Seven patients in group A experienced 13 postoperative hemorrhages. All had received six days of systemic treatment with tranexamic acid. Nine of these bleeding occurrences required replacement therapy with factor VIII/IX:C. In group B, there were no episodes of postoperative bleeding, which was significantly different from group A (p < 0.05). Four patients in group C experienced hemorrhages postoperatively. They had all received preoperative replacement therapy. Five of six bleeding episodes required replacement therapy.
There was a statistically significant reduction in the amount of replacement factor given to the third group in comparison to both of the other groups (p < 0.01). The investigators observed no difference in the number of postoperative hemorrhages with regard to antibiotic prophylaxis. They concluded that treatment with both local and systemic tranexamic acid decreases postoperative hemorrhage in patients with hemophilia. In addition, the authors concluded that requirement for factor VIII/IX:C replacement therapy is reduced in patients treated with tranexamic acid. They also stated that fibrinolysis in the mouth may be a contributor to bleeding after oral surgery and that it may be controlled by oral rinsing with tranexamic acid.7
Adverse reactions
Retinal lesions have been observed in animal studies following either oral or intravenous tranexamic acid at doses of 125-1,600 mg/kg/day. This range represents doses that are three to 40 times higher than the typical human dose of tranexamic acid. The drug was administered anywhere from one week to one year. The occurrence and severity of retinal damage appears to be related to dose and may be reversible at low doses. Retinal alterations have not been observed in human clinical trials; however, vision changes such as blurriness and impaired color vision are the most commonly reported adverse effects.3.5 Hypotension, giddiness, or lightheadedness may occur with rapid intravenous administration.1,4-5 Nausea, vomiting, and diarrhea may occur but usually cease if the dose is reduced.1,3-5 Thromboembolic events1,3 and obstruction of central retinal vessels have been documented.1 Rare occurrences of menstrual discomfort have been reported.3 There have been incidents of ureteric blockage1,8 and renal cortical necrosis associated with use of tranexamic acid.9
Pregnancy/lactation
Tranexamic acid is categorized as pregnancy risk factor B, which is defined by one of the following: 1) no fetal risk has been demonstrated in animal studies but no studies have been performed with pregnant women, or 2) a fetal risk has been observed in animal studies but has not been verified in pregnant women.10 To date, there have been no controlled trials conducted with pregnant human subjects. Transplacental passage of the drug does occur which results in similar serum concentrations of tranexamic acid in cord blood and maternal blood.5,10
Tranexamic acid was used to treat vaginal bleeding in 12 women who were in the final trimester of pregnancy. They received 1 g orally every eight hours for seven days. All 12 delivered healthy babies. Thrombogenesis secondary to tranexamic acid during pregnancy has not been demonstrated. Lactating women who received two days of treatment with the drug displayed breast milk concentrations of tranexamic acid equal to 1% of the serum concentration. The effect of this amount on a nursing infant is unknown.10 Tranexamic acid has been measured in semen, but it does not appear to affect sperm activity.5
Contraindications
Use of tranexamic acid is contraindicated in patients who have color vision abnormalities, subarachnoid hemorrhage,4-5 hematuria, or any history of thrombosis.3
Warnings
Patients should be monitored closely for any signs or symptoms of retinal alterations or visual disturbances. A baseline ophthalmic exam should be performed prior to initiation of therapy and at regular intervals throughout the course of treatment. Any visual changes require discontinuation of the drug. In cases of renal impairment, dosage should be reduced to reduce the risk of medication accumulation. Leukemia related to tranexamic acid occurred in mice who were given doses of 5 g/kg of body weight. Rats who received tranexamic acid for approximately two years in amounts exceeding the maximum tolerated dose experienced increased incidence of hyperplasia and certain tumors of the biliary system. This was not demonstrated in studies performed on another strain of rats. Mutagenicity related to tranexamic acid therapy has not been shown. There have been no controlled studies performed in children. Studies suggest that tranexamic acid may be safely used in the elderly population.3,5
Dosage and administration
Tranexamic acid should be administered in combination with replacement therapy prior to tooth extraction in patients with hemophilia. For intravenous therapy, the recommended dose for prophylaxis immediately before the procedure is 10 mg/kg of body weight. Rate of injection should be 100 mg/min or less.3 Subsequent treatment is administered at the same dose three to four times a day for a period of two to eight days. Doses should be adjusted for renal impairment as outlined in the table below.
| Dosing Adjustment for Tranexamic Acid in Renal Impairment1 |
Drug interactions
Concurrent use of tranexamic acid with anti-inhibitor complex, Factor IX complex1,3 or estrogen-containing products may increase the potential for thrombosis. Thrombolytic agents and tranexamic acid antagonize the effects of each other, therefore efficacy may be decreased if concomitant administration occurs.3
Dosage forms available
The oral formulation of tranexamic acid is no longer available (personal communication, Larry Frigo, Pharmacia and Upjohn, Feb. 18, 2000). The intravenous formulation is supplied in ampules of 10 mL at a concentration of 100 mg/mL. It should be stored at 15° to 30° C and should not be frozen. An oral solution may be prepared as a 1:1 mixture of intravenous tranexamic acid and sterile water. Tranexamic acid is compatible with most components found in intravenous fluids used for infusion (e.g., dextran, electrolytes, carbohydrates, amino acids). Heparin and tranexamic acid are compatible when mixed together. The drug is incompatible in the same solution with penicillin and should not be added to blood products.3
Discussion
Tranexamic acid is approved for prevention or reduction of bleeding and reduction of requirement for replacement therapy in patients with hemophilia who are undergoing tooth extraction. Tranexamic acid controls hemorrhage by inhibiting fibrinolysis and stabilizing fibrin clots.1 Agents similar to tranexamic acid that are currently available include aminocaproic acid11 and desmopressin (DDAVP).12 Aminocaproic acid is indicated for hemorrhage due to fibrinolysis and for bleeding after surgery. It is not currently approved by the FDA for hemorrhage associated with oral and dental surgery in hemophiliac patients.3
DDAVP is approved for use in patients with hemophilia A if serum factor VIII activity levels are greater than 5%. The drug is an effective intraoperative and postoperative hemostatic agent in this patient population. It is not indicated for use in patients with hemophilia B or for any patients with factor VIII activity of 5% or less.13 DDAVP has been used in combination with tranexamic acid for minor hemorrhage induced by fibrinolysis, such as that associated with dental procedures.14
Several clinical trials have documented the efficacy of tranexamic acid for perioperative hemorrhage associated with dental surgery in patients with hemophilia A and B. These studies included a small number of patients. In addition, the number of patients evaluated in the different treatment groups was not well-documented. It should be noted that participants in the studies received oral tranexamic acid and that this formulation is no longer available.
Although an optimal dose of tranexamic acid was not established, the doses utilized in the investigations were effective in reducing bleeding episodes and decreasing the requirement for blood factor replacement. The adverse effects associated with tranexamic acid appear to be mild and are primarily related to high-dose therapy (such as gastrointestinal disturbances) or infusion rate (e.g., hypotension).
Tranexamic acid also has been used for control of intraoperative and postoperative bleeding associated with cardiac surgery. Although this is not currently an FDA-approved use, several studies have demonstrated the effectiveness of tranexamic acid when compared to placebo15 and other agents16 for perioperative hemorrhage.
References
1. Cyklokapron [package insert]. Kalamazoo, MI: Pharmacia and Upjohn; 1999.
2. Dunn CJ, Goa KL. Tranexamic acid: A review of its use in surgery and other indications. Drugs 1999; 57:1,005-1,032.
3. United States Pharmacopeia. United States Pharmacopeia Dispensing Information: Drug Information for the Health Care Professional. 19th ed. Taunton: World Color Book Services; 1999, pp. 2,862-2,865 (tranexamic acid).
4. Mosby Inc. Mosby's GenRx. 9th ed. St. Louis; 1999, pp. II-2,192-II-2,193 (tranexamic acid).
5. St. Louis: Facts and Comparisons. Drug Facts and Comparisons 2000; p. 199 (tranexamic acid).
6. Forbes CD, Barr RD, Reid G, et al. Tranexamic acid in control of haemorrhage after dental extraction in haemophilia and Christmas disease. BMJ 1972; 2:311-313.
7. Sindet-Pedersen S, Stenbjerg S. Effect of local antifibrinolytic treatment with tranexamic acid in hemophiliacs undergoing oral surgery. J Oral Maxillofac Surg 1986; 44:703-707.
8. Swanepoel CR, Cassidy MJD. "Renal Disorders." In: Davies DM, Ferner RE, de Glanville H, eds. Davies's Textbook of Adverse Drug Reactions. London: Chapman and Hall Medical; 1998, pp. 339-380.
9. Curel P, ed. Acute renal cortical necrosis: Case report. Reactions Weekly 1999; 748:12.
10. Briggs G, Freeman R, Yaffe S. Drugs in Pregnancy and Lactation. 5th ed. Baltimore: Williams and Wilkins; 1998.
11. Hudson: Lexi-Comp Inc. MUSC Formulary of Accepted Drugs. Hudson, OH; 1999, pp. 55-56 (aminocaproic acid).
12. Hudson: Lexi-Comp Inc. MUSC Formulary of Accepted Drugs. Hudson, OH; 1999, pp. 228-229 (Desmopressin).
13. Medical Economics Co. Physicians' Desk Reference. 54th ed. Montvale, NJ; 2000, pp. 2,553-2,556.
14. Rodgers GM, Greenberg CS. "Inherited Coagulation Disorders." In: Lee GR, Foerster J, Lukens J, Paraskevas F, et al. Wintrobe's Clinical Hematology. Baltimore: Williams and Wilkins; 1998, pp. 1,682-1,732.
15. Brown RS, Thwaites BK, Mongan PD. Tranexamic acid is effective in decreasing postoperative bleeding and transfusions in primary coronary artery bypass operations: A double-blind, randomized, placebo-controlled trial. Anesth Analg 1997; 85:963-970.
16. Hardy JF, Belisle S, Dupont C, et al. Prophylactic tranexamic acid and g-aminocaproic acid for primary myocardial revascularization. Ann Thorac Surg 1998; 65:371-376.
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