Forr the use of a Registered Medical Practitioner or a Hospital or a Institution only.
TRANEXAMIC ACID TABLETS B.P. (Tranexamic Acid) is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect by blocking lysine-binding sites on plasminogen molecules and thereby inhibiting the interaction of plasminogen and the heavy chain of plasmin with lysine residues on the surface of fibrin. Although plasmin can still be formed under these circumstances, it is unable to bind to and degrade fibrin. Tranexamic acid is 6 to 10 times more potent in terms of binding to plasminogen/plasmin than the other synthetic antifibrinolytic agent E-aminocaproic acid (EACA). Chemically, tranexamic acid is trans-4-(Aminomethyl)cyclohexanecarboxylic acid. The molecular formula is C8H15NO2 and molecular weight is 157.2.
STRUCTURAL FORMULA :
Its structural formula is :
TRANEXAMIC ACID TABLETS B.P. are white coloured, elongated, biconvex, film coated tablets having breakline on one side and plain on other side.
Each film coated tablet contains :
Tranexamic Acid B.P. 500 mg
Colour : Titanium Dioxide B.P.
Tranexamic acid is a competitive inhibitor of plasminogen activation and at much higher concentrations a noncompetitive inhibitor of plasmin, thus implying that tranexamic acid interferes with the fibrinolytic process in the same way as aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid. Tranexamic acid binds considerably more strongly than aminocaproic acid to both the strong and weak 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/ml does not aggregate platelets in vitro. Tranexamic acid in concentrations up to 10 mg/ml blood has no influence on the platelet count, the coagulation time or various coagulation factors in whole blood or citrated blood in normal subjects. On the other hand tranexamic acid in concentrations of 10 mg/ml and 1 mg/ml blood prolongs the thrombin time. Tranexamic acid does not bind to serum albumin. The plasma protein binding is about 3 % at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen.
Absorption from the gastrointestinal tract is only about 50 % at reasonably low oral doses. However, a parallel intake of food has no effect on the gastrointestinal absorption of the drug following a dose of 2 gm or on the maximum plasma concentration.
Tranexamic acid does not bind to serum albumin. The plasma protein binding is about 3 % at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Three hours after a single oral dose of 25 mg/kg, the peak serum level was 15.4 gm/l and the aqueous humour level was 1.6 gm/l. The plasma peak level after 1 gm orally is 8 mg/l and after 2 gm, 15 mg/l, both obtained three hours after dosing. When administered 36 to 48 hours before surgery in 4 doses of 10 to 20 mg/kg, an antifibrinolytically active concentration (10 gm/ml) of tranexamic acid remains in different tissues for about 17 hours and in the serum for up to seven or eight hours. Tranexamic acid passes through to the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to women could be fairly high, about 30 gm/ml of foetal serum. The concentration in breast milk is about one hundredth of the serum peak concentration obtained. Tranexamic acid passes to semen and inhibits its fibrinolytic activity but does not influence the sperm migration. Tranexamic acid crosses the blood-brain barrier. Tranexamic acid concentration in cerebrospinal fluid is about one tenth that of plasma. The drug passes into the aqueous humour, the concentration being about one tenth of the plasma concentration.
Tranexamic acid diffuses rapidly to the joint fluid and the synovial membrane, and in the joint fluid the same concentration is obtained as in the serum. The biological half-life in the joint fluid is about three hours.
Only a small fraction of the drug is metabolised. The total amount of metabolites excreted in urine during 72 hours is less than 5 %. 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.
After an intravenous dose of 1 gm, the plasma concentration time curve shows a triexponential decay with a half life of about 2 hours for the terminal elimination phase. The initial volume of distribution is about 9 to 12 litres.Urinary excretion is the main route of elimination via glomerular filtration. Overall renal clearance is equal to overall plasma clearance (110 to 116 ml/min) and more than 95 % of the dose is excreted in urine as the unchanged drug. Excretion of tranexamic acid by glomerular filtration is about 90 % at 24 hours after intravenous administration of 10 mg/kg bodyweight. After oral administration of 10 to 15 mg/kg body weight the urinary excretion at 24 hours is 39 % and at 48 hours is 41 % of the ingested dose or 78 % of the absorbed material.
TRANEXAMIC ACID TABLETS B.P. are indicated for short term use for haemorrhage or risk of haemorrhage in those with increased fibrinolysis or fibrinogenolysis. Local fibrinolysis as occurs in the following conditions :
1. a) Prostatectomy and bladder surgery
d) Conisation of the cervix
e) Traumatic hyphaema
2. Management of dental extraction in haemophiliacs.
3. Hereditary angioneurotic oedema.
TRANEXAMIC ACID TABLETS B.P. are for oral administration only.
Local Fibrinolysis : The recommended standard dose is 15-25 mg/kg bodyweight (i.e. 2-3 tablets) two to three times daily. For the indications listed below the following doses may be used :
1a Prostatectomy : Prophylaxis and treatment of haemorrhage in high risk patients should commence per- or post-operatively with tranexamic acid injection ; thereafter 2 tablets three to four times daily until macroscopic haematuria is no longer present.
1b Menorrhagia : Recommended dosage is 2 tablets 3 times daily as long as needed for up to 4 days. If very heavy menstrual bleeding, dosage may be increased. A total dose of 4 gm daily (8 tablets) should not be exceeded. Treatment with Tranexamic acid should not be initiated until menstrual bleeding has started.
1c Epistaxis : When repeated bleeding is anticipated oral therapy (2 tablets three times daily) should be administered for 7 days.
1d Cervix Conisation : 3 tablets three times daily.
1e Traumatic Hyphaema : 2-3 tablets 3 times daily. The dose is based on 25 mg/kg three times a day.
2. Haemophilia : In the management of dental extractions 2-3 tablets every eight hours. The dose is based on 25 mg/kg.
3. Hereditary angioneurotic oedema : Some patients are aware of the onset of illness ; suitable treatment for these patients is intermittently 2-3 tablets two to three times daily for some days. Other patients are treated continuously at this dosage.
Paediatrics : In children, the dosage is in the region of 20 mg/kg/day. However, data on efficacy, posology and safety for these indications are limited.
Geriatrics : No reduction in dosage is necessary unless there is evidence of renal failure.
Renal Impairment : By extrapolation from clearance data relating to the intravenous dosage form, the following reduction in the oral dosage is recommended for patients with mild to moderate renal insufficiency :
TRANEXAMIC ACID TABLETS B.P. is contraindicated :
1. In patients with active intravascular clotting process (primary fibrinolysis must be differentiated from disseminated intravascular coagulation)
2. In patients with acquired defective colour vision (used as an indicator of toxicity)
3. In patients with sub-arachnoid haemorrhage (potential occurrence of cerebral ischaemic complications)
4. Hypersensitivity to tranexamic acid
5. Severe renal insufficiency
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 postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, colour 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.
The dose of TRANEXAMIC ACID TABLETS B.P. should be reduced in patients with renal impairment because of the risk of accumulation. Isolated cases of obstruction of the urinary tract due to blood clots have been observed when tranexamic acid has been used to treat severe bleeding from the upper urinary tract. TRANEXAMIC ACID TABLETS B.P. 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 the case of haematuria of renal origin, there is a risk of mechanical anuria due to formation of a ureteral clot. In addition, in cases of massive renal haemorrhage of any cause, antifibrinolytic therapy carries the risk of clot retention in the renal pelvis. Before use of TRANEXAMIC ACID TABLETS B.P., risk factors of thromboembolic disease should be investigated. Although clinical evidence shows no significant increase in thrombosis, possible risk of thrombotic complications cannot be ruled out. 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. A few patients have developed intracranial thrombosis with tranexamic acid but further observation is needed to assess the significance of this potential hazard.
There are no data on the use of TRANEXAMIC ACID TABLETS B.P. in women taking oral contraceptive agents. Tranexamic acid should be administered with care in patients receiving oral contraceptives because of the increased risk of thrombosis. 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. TRANEXAMIC ACID TABLETS B.P. should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Blood in body cavities such as pleural space, joint spaces and urinary tract (e.g. renal pelvis, bladder) may develop ‘indissoluble clots’ in these cavities due to extravascular blood clots which may be resistant to physiological fibrinolysis. Patients with irregular menstrual bleeding should not use tranexamic acid until the cause of the irregularity has been established. If menstrual bleeding is not adequately reduced by tranexamic acid an alternative treatment should be considered. 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.
Pregnancy : Category B
There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta. It appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing mothers : Tranexamic acid is present in the mother’s milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when TRANEXAMIC ACID TABLETS B.P. is administered to a nursing woman.
Paediatric Use : The drug has had limited use in paediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for children can be used for paediatric patients needing tranexamic acid therapy.
Geriatrics : Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of tranexamic acid in the elderly.
INTERACTIONS AND INCOMPATIBILITIES :
Since limited data are available on the co-administration of highly activated prothrombin complex products and antifibrinolytic agents, anti-inhibitor coagulant complex is not to be used concomitantly with tranexamic acid. Tranexamic acid can be mixed with most solutions such as electrolyte, carbohydrate, amino acid, and dextran solutions. It is compatible with heparin. The drug should not be mixed with transfusion blood or with infusion solutions containing penicillin. Concomitant chlorpromazine and tranexamic acid therapy of subarachnoid haemorrhage has been reported to result in cerebral vasospasm and cerebral ischaemia, and possibly a reduction in cerebral blood flow. The sympathomimetic properties of both drugs may have contributed to the development of vasospasm and cerebral ischaemia in these patients. It is best to avoid the combination during treatment of subarachnoid haemorrhage.
SIDE EFFECTS :
Gastrointestinal discomfort occurs in more than 30 % of patients after oral administration of 6 gm/day. The discomfort disappears when the dose is reduced.
Common side effects (1 to < 10 %) : Gastrointestinal tract : Nausea, vomiting, diarrhoea.
Uncommon side effects (0.1 to < 1 %) : Skin and subcutaneous tissue : Allergic skin reactions.
Rare side effects (< 0.1 %) : Thromboembolic events, impaired colour vision and other visual disturbances. Exceptional cases of giddiness have been reported.
OVERDOSAGE AND TREATMENT OF OVERDOSAGE :
No cases of overdosage have been reported. Symptoms may be nausea, vomiting, orthostatic symptoms and/or hypotension. Initiate vomiting, then stomach lavage, and charcoal therapy. Maintain a high fluid intake to promote renal excretion. There is a risk of thrombosis in predisposed individuals. Anticoagulant treatment should be considered.
SHELF LIFE :
24 months from the date of manufacture.
Store below 30°C (86°F), protected from moisture and light.Do not refrigerate.
TRANEXAMIC ACID TABLETS B.P. contains 500 mg of Tranexamic Acid B.P.
3 Blisters of 10 Tablets per box.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.