Tranamic

Yellow capsule shaped, coated biconvex tablets having break line on one side and plain on other side.
Each film-coated tablet contains: Tranexamic Acid BP 500 mg, Mefenamic Acid BP 250 mg.

Anti-Fibrinolytic/Non-Steroidal Anti-Inflammatory Drug.
Pharmacology: Mechanism of Action: Tranexamic acid is a competitive inhibitor of plasminogen activation and at much higher concentrations, a non-competitive 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 concentration 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 from normal subjects. On the other hand, tranexamic acid in concentrations of 10 mg and 1 mg/mL blood prolongs the thrombin time.
Mefenamic acid is an analgesic preparation with anti-inflammatory properties.
Pharmacokinetics: 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. Absorption of tranexamic acid after oral administration in human represents approximately 30 to 50% of the ingested dose. The peak plasma level after 1 g orally is 8 mg/L and 2 g, 15 mg/L, both obtained three hours after dosing.
After an intravenous dose of 1 g, 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 liters. Urinary excretion is the main route of elimination via glomerular filtration. Overall renal clearance is equal to overall plasma clearance (110-116 mL/min) and more than 95% of the dose is excreted in the urine as the unchanged drug. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg/kg body weight. After oral administration of 10 to 15 mg per kg body weight, the cumulative urinary excretion at 24 hours is 39% and at 48 hours, 41% of the ingested dose or 78% and 82% of the absorbed material. Only a small fraction is metabolized. After oral administration, 1% of the dicarboxylic acid and 0.5% of the acetylated compound are excreted.
An antifibrinolytic concentration of tranexamic acid remains in different tissues for about 17 hours and in the serum, up to 78 hours. Tranexamic acid passes through the placenta. The concentration in cord blood after an intravenous injection of 10 mg/kg to pregnant women is about 30 mg/L, as high as in the maternal blood. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. In the joint fluid, the same concentration is obtained as in the serum. The biological half-life of tranexamic acid in the joint fluid is about 3 hours.
The concentration of tranexamic acid in a number of other tissues is lower than in blood. In breast milk, the concentration is about one-hundredth of the serum peak concentration. Tranexamic acid concentration in cerebrospinal fluid is about one tenth of that of the plasma. The drug passes into the aqueous humor, the concentration being about one tenth of the plasma concentration. Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration.
Mefenamic acid is an analgesic preparation with anti-inflammatory properties. Mefenamic acid is known to have a peripheral anti-inflammatory effect and has also shown antipyretic action.
The pharmacological activity of mefenamic acid may be due in part of its ability to inhibit the synthesis of prostaglandins. Mefenamic acid also inhibits the action of exogenous prostaglandins on uterine muscle, uterine tube contraction and ovarian cyclic AMP and progesterone formulation in animal models.
Pharmacokinetics and Metabolism: Mefenamic acid is well absorbed from the gastro-intestinal tract. Peak plasma concentrations occur in about 2 to 4 hours, with a half-life of 2 to 4 hours. Plasma levels are proportional to dose, following multiple doses, with no drug accumulation. Mefenamic acid is extensively bound to plasma proteins. Over 50% of the dose may be recovered in the urine as unchanged drug or conjugated metabolites.

Management of painful bleeding.
Short-term treatment for hemorrhage or risk of hemorrhage in conditions associated with increased fibrinolysis or fibrinogenolysis.
Management of local fibrinolysis as occurs in the following conditions: Prostatectomy and bladder surgery; Menorrhagia; Epistaxis; Conization of the cervix; Traumatic hyphaema; Hereditary angioneurotic edema; Dental extraction in hemophiliacs.
Mefenamic acid: For the relief of mild to moderate pain in acute and chronic conditions including: pain of traumatic, arthritic or muscular origin; primary dysmenorrhoea; headache and dental pain. It is also indicated as an antipyretic in febrile conditions. Mefenamic acid reduces blood loss in menorrhagia where the menorrhagia is due to ovulatory dysfunctional bleeding. Uterine and other pathology should first be excluded before prescribing mefenamic acid this indication.

Adult dose 1 to 1.5 g (or 15 to 25 mg/kg body weight) 2-4 times daily or as prescribed by the physician.

Tranexamic acid: There is no known cause of overdosage. Symptoms of overdosage may be nausea, vomiting, orthostatic symptoms and/or hypotension.
Mefenamic acid: Mefenamic acid has a marked tendency to induce tonic clonic (grand mal) convulsions in overdosage. Dyskinesia, acute renal failure and coma have been reported. Overdose has led to fatalities. Treatment is symptomatic and supportive. Following accidental overdosage, the stomach should be emptied by inducing emesis or gastric lavage followed by administration of activated charcoal. Vital functions should be monitored and supported. Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.

Tranexamic acid is contraindicated in: Acquired defective colour vision: prohibits measuring one endpoint of toxicity.
Subarachnoid haemorrhage: Cerebral edema and cerebral infarction may be caused by tranexamic acid in patients with subarachnoid hemorrhage.
Active intravascular clotting.
Mefenamic acid: Contraindicated in patients with known hypersensitivity. Mefenamic acid should not be given to patients who have experienced asthma, urticaria or allergy-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported.
Other contraindications: Active ulceration or chronic inflammation of either the upper or lower gastrointestinal tract, renal disease with impaired renal or hepatic function and epileptics. Safety in pregnancy and lactation has not yet been established.

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 month in clinical trials.
However, visual abnormalities, often poorly characterized, represents the most frequently reported postmarketing adverse events. 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.
Mefenamic acid: Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding and Perforation: Serious gastrointestinal toxicity, such as inflammation, bleeding, ulceration and perforation of the stomach, small intestine or large intestine, can occur at any time with or without warning symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding, even in the absence of previous GI tract symptoms.
To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Anaphylactoid reactions: As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to mefenamic acid. Mefenamic acid should not be given to patients with the aspirin triad.
Advanced Renal Disease: In case with pre-existing advanced kidney disease, treatment with mefenamic acid is not recommended.
Use in Pregnancy: Mefenamic acid: In late pregnancy, as with other NSAIDs mefenamic acid should be avoided because it may cause premature closure of the ductus arteriosus.

General: Dose should be reduced in patients with renal insufficiency because of risk of accumulation.
Ureteral obstruction due to clot formation in patients with upper respiratory tract bleeding has been reported.
Venous and arterial thrombosis or thromboembolism has been reported. In addition, cases of central retinal artery and central retinal vein obstruction have been reported.
Patients with 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 concentrations or anti-inhibitor coagulant concentrates, as the risk of thrombosis may be increased.
Patients with disseminated intravascular coagulation, who require treatment with tranexamic acid, must be under strict supervision of a physician experienced in treating this disorder.
Carcinogenesis, mutagenesis, impairment of fertility: 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 the 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 non neoplastic, lesions were reported at lower doses. Subsequently 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 invitro and invitro test systems.
Mefenamic acid: General: Mefenamic acid cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
Because mefenamic acid reduces inflammation, it may diminish the diagnostic signs for detecting complications of presumed non-infectious, painful conditions.
Hepatic Effects: Borderline elevations of one or more liver function tests may occur in up to 15% of patients taking NSAIDs, including mefenamic acid. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
Renal Effects: Caution should be used when initiating treatment with mefenamic acid in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with mefenamic acid. Mefenamic acid is not recommended in patients with pre-existing kidney disease.
Long-term administration of mefenamic acid has resulted in renal papillary necrosis and other renal medullary changes. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state.
Mefenamic acid metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied.
Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including mefenamic acid. This may be due to fluid retention, GI loss or an effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including mefenamic acid, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
All drugs, which inhibit the biosynthesis of prostaglandins, may interfere to some extent with platelet function and vascular response to bleeding.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less or shorter duration and reversible. Mefenamic acid dose not generally affect platelet count or partial thromboplastin time (PTT), but may prolong prothrombin time (PT). Patients receiving mefenamic acid who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be careful monitored.
Fluid Retention and Edema: Fluid retention and edema have been observed in some patients taking NSAIDs.
Pre-existing Asthma: Patients with asthma may have aspirin-sensitive asthma. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs have been reported in such aspirin-sensitive patients, mefenamic acid should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Laboratory Tests: Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash, etc.) or if abnormal liver test persist or worsen, Tranexamic Acid and Mefenamic Acid should be discontinued.
Use in Pregnancy: Pregnancy (Category B): Reproduction studies performed in mice, rats and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and 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.
Use in Lactation: 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 is administered to a nursing woman.
Use in Children: Drug has limited use in pediatric patients. Limited data suggest that dosing instructions for adults can be used in pediatric patients.
Mefenamic acid: Safety and effectiveness in pediatric patients below the age of 14 have not been established.
Use in the Elderly: 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.
Mefenamic acid: As with any NSAID, caution should be exercised in treating the elderly (65 years and older).

Pregnancy: Teratogenic Effects: Pregnancy Category C. Reproduction studies have been performed in rats, rabbits and dogs. Rats given up to 10 times the human dose showed decreased fertility, delay in parturition and a decreased rate of survival to weaning. Rabbits at 2.5 times the human dose showed an increase in the number of resorptions. There were no fetal anomalies observed in these studies now in dogs at up to 10 times the human dose.
However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Mefenamic acid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition and decreased pup survival occurred. The effects of mefenamic acid on labor and delivery in pregnant women are unknown.
Nursing Mothers: Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from mefenamic acid a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Tranexamic acid: Gastrointestinal disturbances: Nausea, vomiting, diarrhea, cramps.
Cardiovascular hypotension: Hypotension has been observed especially after rapid I.V. administration. However, this has not been reported with oral administration.
Other: Transient disturbances in colour vision associated with its use.
Musculoskeletal: Malaise, weakness, fatigue, elevated serum enzymes such as creatinine phosphokinase, rhabdomyolysis associated with myoglobinuria and renal failure have been reported.
CNS: Dizziness, tinnitus, headache, delirium, auditory, visual and kinesthetic hallucinations.
Miscellaneous: Conjunctival suffusion, nasal stuffiness, skin rash, reversible acute renal failure, thrombophlebitis.
Worldwide postmarketing report thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid.
Mefenamic acid: The most frequently reported adverse experiences: Gastrointestinal: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting, abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headache, increased bleeding time, pruritus, rash, tinnitus.
Additional adverse experiences reported occasionally: Body as a Whole: Fever, infection, sepsis.
Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope.
Digestive System: Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice.
Hemic and Lymphatic System: Ecchymosis, eosinophilia, leucopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia.
Metabolic and Nutritional: Weight changes.
Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo.
Respiratory System: Asthma, dyspnea.
Skin and Appendages: Alopecia, photosensitivity, pruritus, sweat.
Special Senses: Blurred vision.
Urogenital System: Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure.
Other adverse reactions, which occur rarely: Body as whole: Anaphylactoid reactions, appetite changes, death.
Cardiovascular System: Arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis.
Digestive System: Eructation, liver failure, pancreatitis.
Hemic and Lymphatic System: Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia.
Metabolic and Nutritional: Hyperglycemia.
Nervous System: Convulsions, coma, hallucinations, meningitis.
Respiratory: Respiratory depression, pneumonia.
Skin and Appendages: Angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria.
Special Senses: Conjunctivitis, hearing impairment.

Store at temperatures not exceeding 30°C.

Haemostatics / Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

B02AA02 - tranexamic acid ; Belongs to the class of amino acid antifibrinolytics. Used in the treatment of hemorrhage.
M01AG01 - mefenamic acid ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, fenamates.

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