Tranexamic Acid BOS is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction.

Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of Tranexamic Acid BOS intravenously together with replacement therapy (see section 4.5). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days.

Note: For patients with moderate to severe impaired renal function, the following dosages are recommended:

Serum creatinine μmol/L	Tranexamic Acid Intravenous Dosage
120 to 250 (1.36 to 2.83 mg/dL)	10 mg/kg twice daily
250 to 500 (2.83 to 5.66 mg/dL)	10 mg/kg daily
>500 (>5.66 mg/dL)	10 mg/kg every 48 hours or 5 mg/kg every 24 hours

For intravenous infusion, Tranexamic Acid BOS may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. Heparin may be added to Tranexamic Acid BOS. Tranexamic Acid BOS should NOT be mixed with blood. The drug is a synthetic amino acid and should NOT be mixed with solutions containing penicillin.

Tranexamic Acid BOS is contraindicated: • In patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity (see section 4.5). • In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid in such patients. • In patients with active intravascular clotting. • In patients with hypersensitivity to tranexamic acid or any of the ingredients.

The indications and method of administration indicated above should be followed strictly:
• Intravenous injections or infusion should be given very slowly (maximum 1 mL per minute).
• Tranexamic acid should not be administered by the intramuscular route.

Warnings
Focal areas of retinal degeneration have developed in cats, dogs, and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses, some lesions have appeared to be reversible.
Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks.
No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials.
However, visual abnormalities, often poorly characterized, represent the most frequently reported post marketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground, and visual fields, is advised, before commencing and at regular intervals during the course of treatment.
Tranexamic acid should be discontinued if changes in examination results are found.
Convulsions have been reported in association with tranexamic acid treatment, particularly in patients receiving tranexamic acid during cardiovascular surgery and in patients inadvertently given tranexamic acid into the neuraxial system.
Cases of allergic reaction with use of intravenous tranexamic acid, including anaphylaxis or anaphylactoid reaction have been reported that are suggestive of a causal relationship.

Precautions
The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation (see section 4.1).
Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid.
Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid. In addition, cases of central retinal artery and central retinal vein obstruction have been reported.
Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis.
Tranexamic acid should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased.

Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid, must be under strict supervision of a physician experienced in treating this disorder.

No interaction studies have been performed. Simultaneous treatment with anticoagulants must take place under the strict supervision of a physician experienced in this field. Medicinal products that act on haemostasis should be given with caution to patients treated with tranexamic acid. There is a theoretical risk of increased thrombus-formation potential, such as with oestrogens. Alternatively, the antifibrinolytic action of the drug may be antagonised with thrombolytic drugs.

Women of childbearing potential have to use effective contraception during treatment.

Pregnancy
There are no or limited amount of data from the use of tranexamic acid in pregnant women. As a result, although studies in animals do not indicate teratogenic effects, as precaution for use, tranexamic acid is not recommended during the first trimester of pregnancy.
Limited clinical data of the use of tranexamic acid in different clinical haemorrhagic settings during the second and third trimesters did not identify deleterious effect for the foetus. Tranexamic acid should be used throughout pregnancy only if the expected benefit justifies the potential risk.

Breast-feeding
Tranexamic acid is excreted in human milk. Therefore, breast-feeding is not recommended.

Fertility
There are no clinical data on the effects of tranexamic acid on fertility.

Tranexamic Acid BOS may cause dizziness and therefore may influence the ability to drive or use machines.

The ADRs reported from clinical studies and post-marketing experience are listed below according to system organ class.

Tabulated list of adverse reactions
Adverse reactions reported are presented in table below. Adverse reactions are listed according to MedDRA primary system organ class. Within each system organ class, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

System Organ Class	Common ≥ 1/100 to < 1/10	Uncommon ≥ 1/1,000 to < 1/100	Frequency not known (cannot be estimated from the available data)
Immune system disorders			- Hypersensitivity reactions including anaphylaxis
Nervous system disorders			- Convulsions particularly in case of misuse (refer to sections 4.3 and 4.4)
Eye disorders			- Visual disturbances including impaired colour vision
Vascular disorders			- Malaise with hypotension, with or without loss of consciousness (generally following a too fast intravenous injection, exceptionally after oral administration) - Arterial or venous embolism at any sites
Gastrointestinal disorders	- Diarrhoea - Vomiting - Nausea
Skin and subcutaneous tissue disorders		- Dermatitis allergic

Pediatric Use
The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing tranexamic acid therapy.

Other special population(s)

Geriatric Use
Clinical studies of tranexamic acid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or another drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see section 5 and section 4.2).
To reports any side effect(s):

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the competent authority in Saudi Arabia as per details below:

·         Saudi Arabia

The National Pharmacovigilance Centre (NPC) ·         - SFDA Call Centre: 19999 ·         - E-mail: npc.drug@sfda.gov.sa ·         - Website: https://ade.sfda.gov.sa/

·         Other GCC States

·         Please contact the relevant competent authority.

Cases of overdosage of tranexamic acid have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic, e.g., arterial, venous, embolic; neurologic, e.g., visual impairment, convulsions, headache, mental status changes; myoclonus; and rash.

Pharmacotherapeutic group: Antihemorrhagics, Antifibrinolytics, Aminoacids
ATC code: B02AA02

Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid.
Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. Tranexamic acid in a concentration of 1 mg per mL does not aggregate platelets in vitro.
Tranexamic acid, in concentrations as low as 1 mg per mL, can prolong the thrombin time. However, tranexamic acid in concentrations up to 10 mg per mL in blood showed no influence on the platelet count, the coagulation time, or other coagulation factors in whole blood or citrated blood from normal subjects.

Absorption
Peak plasma concentrations of tranexamic acid are obtained rapidly after a short intravenous infusion after which plasma concentrations decline in a multi-exponential manner.

Distribution
The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic acid does not bind to serum albumin. The initial volume of distribution is about 9 to 12 litres.
Tranexamic acid passes through the placenta. Following administration of an intravenous injection of 10 mg/kg to 12 pregnant women, the concentration of tranexamic acid in serum ranged 10-53 μg/mL while that in cord blood ranged 4- 31 μg/mL. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. Following administration of an intravenous injection of 10 mg/kg to 17 patients undergoing knee surgery, concentrations in the joint fluids were similar to those seen in corresponding serum samples. The concentration of tranexamic acid in a number of other tissues is a fraction of that observed in the blood (breast milk, one hundredth; cerebrospinal fluid, one tenth; aqueous humor, one tenth). Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration.

Elimination
It is excreted mainly in the urine as unchanged drug. Urinary excretion via glomerular filtration is the main route of elimination. Renal clearance is equal to plasma clearance (110 to 116 mL/min). Excretion of tranexamic acid is about 90% within the first 24 hours after intravenous administration of 10 mg/kg body weight.
Elimination half-life of tranexamic acid is approximately 3 hours.

An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment.
Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses.
Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic / neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitro and in vivo test systems.
There are no clinical data to assess the effects of tranexamic acid on fertility.

Water for injections

Tranexamic Acid BOS should not be added to blood for transfusion, or to injections containing penicillin.

24 months After first opening: the solution for injection is for single use only. Unused solution for injection must be discarded. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store below 30°C

Do not freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

Tranexamic Acid BOS is a clear, colorless solution for Injection containing 100 mg/mL of Tranexamic Acid. The product is filled as 1000 mg in 10 mL USP Type I Clear Glass Ampoule.

Tranexamic Acid BOS may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, Amino acid solutions and Dextran solutions. The solution should be prepared the same day the solution is to be used.
Tranexamic Acid BOS is for single use only.
Discard tranexamic acid injection vial or ampule and any remaining portion in the vial/ampule after single use.