- PRESCRIBING INFORMATION - PRODUCT MONOGRAPH - ERFA TRANEXAMIN
Tranexamic Acid Injection, Ph. Eur.
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 body weight gave plasma concentrations of 18.3 µg, 9.6 µg and 5 µg 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 µg/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 µg 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
Increased local fibrinolysis when the diagnosis is indicative of hyperfibrinolysis as in dental extraction in patients with coagulopathies (in conjunction with antihaemophilic factor).
Patients with a history or risk of thrombosis should not be given tranexamic acid, 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 color vision. If disturbances of vision arise during the course of treatment the administration of the preparation should be discontinued.
Patients with active thromboembolic disease, such as deep vein thrombosis, pulmonary embolism and cerebral thrombosis.
Patients with subarachnoid hemorrhage: the limited clinical experience shows that a reduced risk for re-bleeding is offset by an increase in the rate of cerebral ischaemia.
Haematuria ( see WARNINGS and PRECAUTIONS). Hypersensitivity to tranexamic acid or any of the ingredients.
Visual disturbances including visual impairment, vision blurred, impaired color vision have been reported with tranexamic acid. For patients who are to be treated for several weeks with tranexamic acid, an ophthalmic check-up is advisable (sharpness of vision, color vision, fundus, field of vision, etc.), if possible, before treatment is initiated and regularly during treatments.
Patients with irregular menstrual bleeding should not use tranexamic acid until the cause of the irregularity has been established.
Patients should consult their doctor if menstrual bleeding is not reduced after three menstrual cycles.
If menstrual bleeding is not adequately reduced by tranexamic acid, an alternative treatment should be considered.
Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid. Patients with a high risk for thrombosis (a previous thromboembolic event and a family history of thromboembolic disease) should use tranexamic acid only if there is a strong medical indication and under strict medical supervision.
Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid, must be under the strict supervision of a physician experienced in treating this disorder.
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.
Convulsions have been reported in association with tranexamic acid treatment.
Hormonal Contraceptives: Combination hormonal contraceptives are known to increase the risk of venous thromboembolism, as well as arterial thromboses such as stroke and myocardial infarction. Because tranexamic acid is an antifibrinolytic, concomitant use of hormonal contraception and tranexamic acid may further exacerbate this increased thrombotic risk.
Women using hormonal contraception should use tranexamic acid only if there is a strong medical need and the benefit of treatment will outweigh the potential increased risk of a thrombotic event (see DRUG INTERACTIONS).
Patients taking anticoagulants (see DOSAGE and ADMINISTRATION)
Use in pregnancy: The safety of tranexamic acid 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 arrested 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 µg 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 wide experience with tranexamic acid in connection with childbirth have observed no negative effect on the infants.
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 (see DOSAGE and ADMINISTRATION).
The following patients should consult their doctor prior to initiating treatment with tranexamic acid: obese and diabetic, with polycystic ovary syndrome or a history of endometrial cancer in a first degree relative, women receiving unopposed oestrogen or tamoxifen.
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.
: Clinical experience with tranexamic acid in menorrhagic children under 18 years of age is not available.
Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines.
No studies of interactions between tranexamic acid and other drugs have been conducted. Because of the absence of interaction studies, simultaneous treatment with anticoagulants must take place under the strict supervision of a physician experienced in this field.
Potential drug-drug interactions leading to myocardial infarction after coadministration with hormonal contraceptives, hydrochlorothiazide, desmopressin, sulbactam-ampicillin, carbazochrome, ranitidine, or nitroglycerin.
Because tranexamic acid is an antifibrinolytic, concomitant use of hormonal contraception and tranexamic acid may further exacerbate the increased thrombotic risk associated with combination hormonal contraceptives (see WARNINGS).
- ADVERSE REACTIONS
Gastrointestinal Disorders: Gastrointestinal symptoms (nausea, vomiting, diarrhea) occur but disappear when the dose is reduced.
Nervous System Disorders: Isolated cases of dizziness or reduced blood pressure have been reported.
Immune System Disorders: allergic dermatitis have been reported less commonly.
To be observed by reason of experimental findings in animals: In the dog retina changes have been observed after long-term administration of large doses of tranexamic acid and in the cat, after intravenous injection of 250 mg per kg body weight per day for 14 days. Such changes have not been obtained in the rat, where the maximum tolerated dose has 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.
Rare cases of adverse events have been reported with the use of tranexamic acid:
Vascular Disorders: thromboembolic events (acute myocardial infarction, thrombosis, arterial thrombosis limb, carotid artery thrombosis, cerebral infarction, cerebrovascular accident, deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction). Hypotension may occur after fast injection.
Eye Disorders: impaired vision, blurred vision or color vision impairment (chromatopsia)
Nervous System Disorders: dizziness and seizures.
- SYMPTOMS AND TREATMENT OF OVERDOSAGE
There is no known case of overdosage of tranexamic acid in humans. Symptoms may be nausea, diarrhoea, dizziness, headache, convulsions, vomiting, orthostatic symptoms and hypotension. Treatment of overdosage would consist of initiating vomiting, institution of gastric lavage, charcoal therapy, and symptomatic treatment. Maintain adequate diuresis.
For management of a suspected drug overdose, contact your Regional Poison Control Centre immediately.
- DOSAGE AND ADMINISTRATION
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 ERFA-TRANEXAMIC intravenously per kg body weight. After the operation, tranexamic acid tablets are usually given and the patient does not generally require further substitution therapy.
Administration: ERFA-TRANEXAMIC is intended for intravenous administration (intravenous injection and infusion). ERFA-TRANEXAMIC should be administered intravenously by slow injection over a period of at least 5 minutes. The recommended rate of bolus infusion is 50 mg/min. To administer 50 mg/min to the patient directly via intravenous injection, 0.5 mL/min of undiluted ERFA-TRANEXAMIC (100 mg/mL) should be administered by slow intravenous injection. To administer 50 mg/min as an infusion, solutions diluted to 1% tranexamic acid (i.e. 1 g in 100 mL or 10 mg/mL), may be administered at
5 mL/min or solutions diluted to 2% tranexamic acid, may be administered at 2.5 mL/min.
For intravenous infusion ERFA-TRANEXAMIC injection may be mixed with:
- electrolyte solutions (e.g. 0.9% NaCl solution, Ringer’s solution),
- carbohydrate solutions (e.g. 5% glucose solution),
- amino acid solutions and
- dextran solutions (e.g. dextran 40).
Heparin may be added to ERFA-TRANEXAMIC. ERFA-TRANEXAMIC should not be mixed with blood and infusion solutions containing penicillin.
The required volume of ERFA-TRANEXAMIC may be added to the chosen infusion solution to achieve final concentrations of 1 or 2 g in 100 mL (10 or 20 mg/mL, 1 % or 2 %). A solution with a 100 mL final volume would be prepared as shown in the table below:
Preparation of infusion solutions Solution 1 % (10 mg/mL) Solution 2 % (20 mg/mL) Tranexamic acid (g) 1 g 2 g Compatible diluents* qsp 100 mL qsp 100 mL
*See above for compatible diluents.
NB: 1 g of tranexamic acid is obtained from 1 vial of 10 mL or 2 vials of 5 mL;
2 g of tranexamic acid are obtained from 2 vials of 10 mL or 4 vials of 5 mL.
An example of preparation and administration of a solution for intravenous infusion is summarized in the table below:
Infusion rates for undiluted and diluted tranexamic acid solutions
Bolus (50 mg/min) Undiluted solution (100 mg/mL) Diluted solution 1 % (10 mg/mL) 2 % (20 mg/mL) Infusion rate - 0.5 mL/min 5 mL/min 2.5 mL/min Example of a patient dosed at 10 mg/kg 70 7 mL (14 mins) 70 mL (14 mins) 35 mL (14 mins)
The mixture should be used immediately after preparation. If storage is necessary, the mixture should be stored refrigerated between 2 to 8oC for a maximum of 24 hours. Mixture not used within 24 hours of preparation, should be discarded.
The vials of ERFA-TRANEXAMIC are sterile. ERFA-TRANEXAMIC is intended for single use. Unused product must be discarded. As with all parenteral drug products, ERFA-TRANEXAMIC should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration, whenever solution and container permit.
Patients with Impaired Renal Function: In patients with serum creatine concentrations of 120 to 250 µmol/L, 10 mg intravenously tranexamic acid per kg body weight twice daily. At serum creatine levels of 250 to 500 µmol/L the dosage should be 10 mg intravenously per kg body weight at 24-hourly intervals, and at serum creatine levels of 500 µmol/L or more, the same dose should be given at intervals of 48 hours between doses.
- PHARMACEUTICAL INFORMATION
Drug Substance: Tranexamic acid
INN Name: Tranexamic acid
Chemical name: trans-4 (aminomethyl) cyclohexanecarboxylic acid
Molecular formula: C8H15NO2
Molecular weight: 157.2 g/mol
Physical Form: A white crystalline powder odorless or almost odorless.
Solubility: Tranexamic acid is freely soluble in water.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Each mL of ERFA-TRANEXAMIC contains: tranexamic acid 100 mg, sodium hydroxide and/or hydrochloric acid to adjust pH and water for injection.
pH: ERFA-TRANEXAMIC solution for injection has pH 6.5-8.
ERFA-TRANEXAMIC, 100 mg/mL, is preservative free and available in 5 mL and 10 mL, boxes of 10 and 50 mL, boxes of 1 single use vials,
STORAGE AND STABILITY
Store between 15 and 30°C. Discard unused portion. Protect from light.
Mixture must be kept refrigerated between 2 and 8oC for not more than 24 hours. Mixture not used within 24 hours of preparation, should be discarded.
LATEX FREE STOPPER: Stopper contains no dry natural rubber.
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 terminated by 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 55mg/kg tranexamic acid in the feed.
An intravenous dose of 50 mg/kg of tranexamic acid decreases pulmonary fibrinolysis in the rat. 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 (5 x 10-2 M) competitively inhibits the activation of trypsinogen by enterokinase and non-competitively inhibits the proteolytic activity of trypsin at 4-fold greater concentration (e.g. 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 (7 x 10-3 M, 100 mg/L Andersson et al, 1965). Tranexamic acid (7 x 10-2 M) 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 (7 x 10-3 M, l g/L) does not aggregate human platelets in vitro. On the contrary in vivo (dogs) a dose of 30 mg/kg IV 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, 6 x 10-3 M. The degradation of bradykinin in human plasma is not significantly inhibited at 10-2 M.
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.
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 exceed 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.
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 1 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 thrombophlebitis in the urinary bladder. No cardiac hemorrhages were found.
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 ciliaris 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 about30 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) occurred 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.
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- Sheffer AL, Fearon DT, Austen KF, Rosen FS. Tranexamic acid: Pre-operative prophylactic therapy for patients with hereditary angioneurotic J. Allerg Clin Immunol 1977; 60: 38-40.
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- Pfizer Canada Inc. Product Monograph: Cyklokapron. Control No.: 185812 . Date of preparation: February 22, 2016. .
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