SABEX 2002 INC. Date of preparation: September 5, 2002 145 Jules-Leger Street Revision Date: February 09, 2004 Boucherville, QC J4B 7K8 Control No. 087810

PRODUCT MONOGRAPH

mg/mL Antifibrinolytic Agent

ACTIONS AND CLINICAL PHARMACOLOGY

Tranexamic acid produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. It is also a weak non-competitive inhibitor of plasmin. These properties make possible its clinical use as an antifibrinolytic in the treatment of both general and local fibrinolytic hemorrhages. It has an action mechanism similar to, but about 10 times more potent in vitro, than that of E amino caproic acid (EACA). Tranexamic acid binds considerably more strongly than EACA to both the strong and weak sites in the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. The pharmacological significance of the binding to these different sites has not yet been evaluated. Tranexamic acid does not bind to serum albumin. The plasma protein binding seems to be fully accounted for by its binding to plasminogen and appears to be negligible at therapeutic plasma levels of 5-10 mg/L. Possible routes of biotransformation are acetylation or deamination followed by oxidation or reduction. After oral administration approximately 50% of the parent compound, 2% of the deaminated dicarboxylic acid, and 0.5% of the acetylated product are excreted. Tranexamic acid is eliminated by glomerular filtration, excretion being about 30% at one hour, 55% at three hours and 90% at 24 hours after intravenous administration of 10 mg per kg body weight. After oral administration of 10-15 mg per kg body weight excretion was 1% at one hour, 7% at three hours and 39% at 24 hours. Intravenous administration of 10 mg per kg weight gave plasma concentrations of 18.3 mcg, 9.6 mcg and 5 mcg per mL one, three and five hours after the injection. When administered 36-48 hours before surgery in four doses of 10-20 mg per kg body weight, an antifibrinolytically active concentration (10 mcg/mL) of tranexamic acid remained up to 17 hours in the tissues investigated, and up to 7-8 hours in the serum (Andersson et al, 1968). Tranexamic acid crosses the placenta. After an intravenous injection of 10 mg per kg, the concentration can rise to about 30 mcg per mL of fetal serum. Tranexamic acid also passes over into the breast milk during lactation in concentrations 1/100 of the corresponding serum levels. After both oral and intravenous administration tranexamic acid passes into the semen and inhibits its fibrinolytic activity, but without affecting the motility of the spermatozoa (Liedholm, 1973). The ability of tranexamic acid to cross the blood-brain barrier has been demonstrated when administered to patients with ruptured intracranial aneurysms. Tranexamic acid diffuses rapidly to the joint fluid and to the synovial membrane. In the joint fluid the same concentration was obtained as in the serum. The biological half-life in the joint fluid was about 3 hours.

INDICATIONS AND CLINICAL USE

Tranexamic acid is indicated for increased local fibrinolysis when diagnosis is indicative of hyperfibrinolysis as in dental extraction in patients with coagulopathies (in conjunction with antihaemophilic factor).

CONTRAINDICATIONS

Patients with a history or risk of thrombosis should not be given Tranexamic Acid Injection BP, unless at the same time it is possible to give treatment with anticoagulants. The preparation should not be given to patients with acquired disturbances of colour vision. If disturbances of colour vision arise during the course of treatment the administration of the preparation should be discontinued.

WARNINGS

For patients who are to be treated for several weeks with Tranexamic Acid Injection BP, an ophthalmic check-up is advisable (sharpness of vision, colour vision, fundus, field of vision, etc.) If possible, before treatment is initiated and regularly during treatments.

Use in pregnancy

The safety of Tranexamic Acid Injection BP during pregnancy has not yet been established. No harmful effects have been reported. A woman with fibrinolytic bleeding in the fourth month of pregnancy was treated with tranexamic acid for a total of 64 days. The total dose was 256 g. The delivery occurred spontaneously in the 30th week of pregnancy and was normal in all other respects. The infant was healthy. In a case of threatened placental abruption that was prevented by giving tranexamic acid, the patient had already lost two children in connection with placental abruption. In the 26th week of her third pregnancy bleeding occurred, indicating abruption. Pathological proteolysis with predominant activation of the fibrinolytic system was established. Between the 26th and 33rd week of pregnancy about 250 g of tranexamic acid were given, both intravenously and orally. The bleeding was stopped and a healthy child was delivered by Caesarean section. Tranexamic acid crosses over to the fetus (Kullander and Nilsson, 1970). After an IV injection of 10 mg per kg the concentration can reach a level of about 30 mcg per mL fetal serum. Fibrinolytic activity is very high in neonates. It is not known for certain whether a reduction of this activity during the first hours of life is harmful. Kullander and Nilsson who have a wide experience with tranexamic acid in connection with childbirth have observed no negative effect on the infants.

PRECAUTIONS

Care should be taken in cases of renal insufficiency due to the risk of accumulation, and where there is pronounced haematuria from the upper urinary tract, since in isolated cases obstacles to passage have been observed in the tract. Tranexamic acid therapy is not indicated in haematuria caused by diseases of the renal parenchyma. Intravascular precipitation of fibrin frequently occurs in these conditions and may aggravate the disease. In addition, in cases of massive renal hemorrhage of any cause, antifibrinolytic therapy carries the risk of clot retention in the renal pelvis.

Nursing Mothers:

Tranexamic acid is secreted in the mother's milk at a concentration only a hundredth of the corresponding serum levels (Eriksson et al, 1971). The investigators are of the opinion that tranexamic acid can be given during lactation without risk to the child.

ADVERSE REACTIONS

Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur but disappear when the dose is reduced. Isolated cases of dizziness or reduced blood pressure have been reported.

To be observed by reason of experimental findings in animals:

In dogs retina changes have been observed after long-term administration of large doses of tranexamic acid and in cats, after intravenous injection of 250 mg per kg body weight per day for 14 days. Such changes have not been observed with rats, when the maximum tolerated dose had been administered. No retinal changes have been reported or observed at ophthalmic check-ups of patients treated with tranexamic acid for several weeks or months.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There is no known case of overdosage of tranexamic acid in humans. Symptoms may be nausea and vomiting, orthostatic symptoms and hypotension. Treatment of overdosage would consist of initiating vomiting, institution of gastric lavage and charcoal therapy.

DOSAGE AND ADMINISTRATION

The following dosage scheme can be recommended: In patients with serum creatine concentrations of 120 to 250 :mol/L, 10 mg intravenously tranexamic acid per kg body weight twice daily. At serum creatine levels of 250 to 500 :mol/L the dosage should be 10 mg intravenously per kg body weight at 24-hourly intervals, and at serum creatine levels of 500 :mol/L or more, the same dose should be given at intervals of 48 hours between doses. Dental surgery in patients with coagulopathies: 2 hours before the operation, Factor VIII and Factor IX should be given as well as 10 mg of Tranexamic Acid Injection BP intravenously per kg body weight or alternatively oral administration with tranexamic acid tablets is possible. After the operation, tranexamic acid tablets are usually given. Also, after the operation the patient does not generally require further substitution therapy.

INTRAVENOUS ADMINISTRATION

Tranexamic Acid Injection BP is administered intravenously by slow injection over a period of at least 5 minutes. For intravenous infusion Tranexamic Acid Injection BP is compatible and stable for 24 hours at room temperature when diluted to 2 mg/mL with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection in polyvinyl chloride (PVC bags). Heparin may be added to Tranexamic Acid Injection BP. Tranexamic Acid Injection BP should not be mixed with blood and infusion solutions containing penicillin.

PHARMACEUTICAL INFORMATION

Proper or Common Name :

Chemical Name:

Structural Formula.

Molecular Weight:

Physical Form:

Solubility:

Tranexamic acid is freely soluble in water and glacial acetic acid; very slightly soluble in ethanol; pratically insoluble in alcohol, acetone and ether.

pH Melting point: COMPOSITION

Each mL of Tranexamic Acid Injection BP contains: tranexamic acid 100 mg, sodium hydroxide and/or hydrochloric acid to adjust pH and water for injection.

STABILITY AND STORAGE RECOMMENDATIONS

PREPARATION OF IV SOLUTION

Dilution for continuous intravenous infusion

Tranexamic Acid Injection BP is compatible and stable for 24 hours at room temperature when diluted to 2 mg/mL with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection in polyvinyl chloride (PVC) bags. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

Pharmacy Bulk Vial

The use of Pharmacy Bulk Vials is restricted to hospitals with a recognized parenteral admixture program. The Pharmacy Bulk Vial is intended for single puncture, multiple dispensing and for the preparation of admixtures only. Dispensing from a Pharmacy Bulk Vial should be completed as soon as possible after initial entry.

AVAILABILITY OF DOSAGE FORMS

Tranexamic Acid Injection BP, 100 mg/mL, is preservative-free and available in 5 mL ampoules, boxes of 10, 5 mL and 10 mL single use glass vials, boxes of 10, and 50 mL Pharmacy Bulk Vials, boxes of 1.

PHARMACOLOGY

The therapeutic plasma concentration of tranexamic acid is 5-15 mg/L. The functional interaction between plasminogen and tissue activator, located mainly on fibrin, is prevented by dissociation of the complex between fibrin and specific substrate binding sites on plasminogen a potentiating effect on natural inhibitors also appears to contribute to the clinical effect during antifibrinolytic therapy.

Antifibrinolytic Effect In Vivo

Thirty minutes after hyperfibrinolytic states have been produced by injection of streptokinase in rabbits, fibrinolysis was immediately ended with an intravenous dose of 30 mg/kg of tranexamic acid, compared to a 3-10 times higher dose of 100-300 mg/kg E amino caproic acid (EACA) necessary to obtain comparable effects. Dogs show an immediate 40% decrease in urinary urokinase excretion at an oral dose of 55 mg/kg tranexamic acid in the feed. An intravenous dose of 50 mg/kg of tranexamic acid decreases pulmonary fibrinolysis in rats. Maximum inhibition occurred 5-15 minutes after injection of 600 mg/kg and the effect lasted for 8 hours.

Influence on Other Enzyme Mechanisms

Tranexamic acid (5x10-2 M) competitively inhibits the activation of trypsinogen by enterokinase and non-competitively inhibits the proteolytic activity of trypsin at 4-fold greater concentration ( Dubber et al, 1965). While aminocaproic acid moderately inhibits trypsin (40%), urinary kallikrein (30%) and pancreatic kallikrein (60%), tranexamic acid has little effect (less than 10%) on any of these enzymes. A still weaker effect is exerted on thrombin (7x10-3M, 100 mg/L ; Andersson et al, 1965). Tranexamic acid (7x10-2M ) added to blood has no influence on the platelet count, coagulation time, one-stage prothrombin time or recalcification time. The plasma levels of AHF, Factor IX, prothrombin, Factor VII, Factor V and fibrinogen also remain unchanged in vitro. Tranexamic acid (7x10-3M, l g/L) does not aggregate human platelets in vitro. On the contrary in vivo (dogs) a dose of 30 mg/kg i.v. showed a decreased ADP-induced aggregability and a stabilizing effect on glass bead adhesiveness for 24 hours after the administration (Jong, 1974). The activity of chymotrypsin is not impaired by synthetic antifibrinolytics and an inhibition of the action of pepsin is observed only in high concentrations, 6x10-3M. The degradation of bradykinin in human plasma is not significantly inhibited at 10-2M.

Interaction with the Cardiovascular System

Tranexamic acid administered by IV infusion in the anaesthetized cat in doses of 0.4-2 mg/kg/min. for 60 minutes and IM in the rabbit, cat and dog in doses of 170 mg/kg do not cause significant changes in arterial blood pressure, respiration of ECG (Marmo et al, 1973). The mechanism of the cardiovascular effect of tranexamic acid is less clear than that of E-amino caproic acid, which appears to produce an indirect sympathomimetic effect. In relation to its therapeutic effect tranexamic acid has about 10 times less potent effect than EACA on blood pressure. Threshold doses to produce increase in the blood pressure and heart rate are 50-100 mg/kg for tranexamic acid and 30-50 mg/kg for EACA in anaesthetized cats.

TOXICITY

Acute Toxicity

The acute toxicity of tranexamic acid was studied over 24 hours and 7 days in mice and rats and 24 hours, 48 hours and 7 days in rabbits, following intravenous, intraperitoneal, subcutaneous and oral administration. In a fourth study, mortality was examined 72 hours after intravenous, oral and subcutaneous administration. The lethal oral doses exceeded 5-10 g/kg body weight in all studied species and the LD50 values after intravenous injection were about 1-1.5 g/kg body weight in mice, rats and dogs.

Subacute Toxicity

In six subacute toxicity studies, daily doses of tranexamic acid were administered: orally to rats (1 to 5 g/kg for 10 weeks) and dogs (100 to 500 mg/kg for 4 months); intravenously to dogs (20-500 mg/kg for 1 month and 1 g/kg for 3 days) and to rabbits (60-180 mg/kg for 13 days); and intraperitoneally to rats (0-1000 mg/kg for 2 weeks). Dose-related emesis, loose stools or diarrhea, and decreased body weight gain were the only observed drug induced findings in the oral and intraperitoneal studies. In intravenous administration to rabbits, the only clinical finding was dose-related tachypnea. In the intravenous short-term (3-day) study, one dog vomited frequently during the first infusion and at the end of the infusion convulsed and died. At necropsy, this dog had a small hemorrhage in the heart and histological examination showed heart petechiae. In the one- month intravenous study in dogs given 20, 100 or 500 mg/kg/day (Balazs & Porpora, 1969, Ohtake & Kepenis, 1969) emesis and salivation occurred at the two highest dose levels. Microscopically, pulmonary thromboembolism was found in one dog receiving the intermediate dose and one from the high dose group. The latter dog also had two thrombophletitides in the urinary bladder. No cardiac hemorrhages were found.

Chronic Toxicity

In eight chronic toxicity studies, tranexamic acid was administered: orally to rats (0-4000 mg/kg/day for 1 year), to dogs (200-1600 mg/kg/day and 800-1200 mg/kg/day for 1 year); in the diet to rats (0-4.8% for 22 months and 0-5% for 19 months) and to rats and mice (4.8% for 20 months); subcutaneously to mice (0.8-1.5 mg single injection observed for 1 year) and subcutaneously (0-3.5 g/kg/wk) or orally (0-10 g/kg/wk) to rats for 2 years. At extremely high dose levels of 2 x 400 mg/kg/day and peak plasma levels of about 200 mg per litre, in chronic oral toxicity studies in dogs, atrophy in the anterior (ora ciliniaris retinae) and posterior (around the optic disc) retina have been observed. The atrophic retinal changes are similar to those observed in senescence in dogs and man. In man, peak plasma levels are in the range of 10- 20 mg per litre after a therapeutic oral dose of about 30 mg/kg body weight. Similar changes have been produced in high level daily intravenous infusion of tranexamic acid in dogs and cats. Eye damage was not established in the life-long feeding study (carcinogenicity study) performed in rats. In one of the carcinogenicity studies in which rats were given tranexamic acid in high doses, biliary hyperplasia, cholangioma and adenocarcinoma of the liver were found. These findings have not been reproduced in a number of subsequent carcinogenicity studies. An increased incidence of leukemia (although not statistically significant) was reported in one study in mice given 4.8 percent tranexamic acid for 20 months. In other studies, the frequency and histologic appearance of the observed tumors were similar in the test groups and in the untreated animals.

TRANEXAMIC ACID INJECTION BP	Volume of Compatible IV Solution	Final Volume	Final Concentration
1 mL	50 mL	51 mL	2 mg/mL

mg/mL

Antifibrinolytic Agent