Package Insert. Dubix K

Transcription

1 Package Insert Dubix K Product Summary 1. Name of the medicinal product Dubix K 2. Qualitative and quantitative composition Each film coated tablet contains: Tranexamic Acid B.P. 500 mg Mefenamic Acid I.P. 325 mg Vitamin K 5 mg 3. Pharmaceutical form Film coated tablet 4. Clinical particulars 4.1 Therapeutic indications Tranexamic acid This is indicated for short term use for haemorrhage or risk of haemorrhage in those with increased fibrinolysis or fibrino-genolysis. Local fibrinolysis as occurs in the following conditions: 1. a) Prostatectomy and bladder surgery b) Menorrhagia c) Epistaxis d) Conisation of the cervix e) Traumatic hyphaema 2. Management of dental extraction in haemophiliacs. 3. Hereditary angio-neurotic oedema. 16 th May 2016 Dubix K 1

2 Mefenamic acid This is a non-steroidal anti-inflammatory agent with analgesic properties, and a demonstrable antipyretic effect. It has been shown to inhibit prostaglandin activity. Indications 1. As an anti-inflammatory analgesic for the symptomatic relief of rheumatoid arthritis (including Still's Disease), osteoarthritis, and pain including muscular, traumatic and dental pain, headaches of most aetiology, post-operative and post-partum pain. 2. Primary dysmenorrhoea. 3. Menorrhagia due to dysfunctional causes and presence of an IUD when other pelvic pathology has been ruled out. Vitamin K This is indicated in the following coagulation disorders which are due to faulty formation of factors II, VII, IX and X when caused by vitamin K deficiency or interference with vitamin K activity. Vitamin K is indicated in: anticoagulant-induced prothrombin deficiency caused by coumarin or indanedione derivatives; hypoprothrombinemia secondary to antibacterial therapy; hypoprothrombinemia secondary to administration of salicylates; hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas but only if bile salts are administered concurrently, since otherwise the oral vitamin K will not be absorbed. 4.2 Posology and method of administration Dubix K should be taken as prescribed by the physician. The recommendations for the individual components in Dubix K are Tranexamic acid Posology Adults Local Fibrinolysis: The recommended standard dose is 15-25mg/kg bodyweight two to three times daily. For the indications listed below the following doses may be 16 th May 2016 Dubix K 2

3 used: 1a Prostatectomy: Prophylaxis and treatment of haemorrhage in high risk patients should commence pre- or post-operatively with tranexamic acid injection; thereafter oral daily until macroscopic haematuria is no longer present. 1b Menorrhagia: Recommended dosage is as prescribed by the physician. If very heavy menstrual bleeding, dosage may be increased. A total dose of 4g daily 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 (15mg/kg) should be administered for 7 days. 1d Cervix Conisation: 25mg/kg three times daily. 1e Traumatic Hyphaema: 15-25mg/kg 3 times daily. 2. Haemophilia: In the management of dental extractions mg/kg every eight hours. The dose is based on 25mg/kg. 3. Hereditary angio-neurotic oedema: Some patients are aware of the onset of illness; suitable treatment for these patients is intermittently mg/kg two to three times daily for some days. Other patients are treated continuously at this dosage. Paediatric population In children, for current approved indications as described in section 4.1, the dosage is in the region of 20 mg/kg/day. However, data on efficacy, posology and safety for these indications are limited. Older patients No reduction in dosage is necessary unless there is evidence of renal failure (see guidelines below). Renal insufficiency 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: Serum Creatinine (μmol/l) Oral Dose Dose Frequency mg/kg body weight twice daily mg/kg body weight daily 16 th May 2016 Dubix K 3

4 Mefenamic acid Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4) Adults In menorrhagia to be administered on the first day of excessive bleeding and continued according to the judgement of the physician. In dysmenorrhea, to be administered at the onset of menstrual pain and continued according to the judgement of the physician. Elderly (over 65 Years) As for adults. Whilst no pharmacokinetic or clinical studies specific to the elderly have been undertaken with Mefenamic acid, it has been used at normal dosage in trials which included many elderly patients. The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. Mefenamic acid should be used with caution in elderly patients suffering from dehydration and renal disease. Non-oliguric renal failure and proctocolitis have been reported mainly in elderly patients who have not discontinued mefenamic acid after the development of diarrhoea. Children It is recommended that children under 12 years of age should be given Mefenamic Acid Suspension (50mg/5ml).Do not exceed the stated dose. Mefenamic acid tablets should be taken preferably with or after food. Vitamin K Adults Anticoagulant-Induced Prothrombin Deficiency (caused by coumarin or indanedione derivatives) Hypoprothrombinemia due to other causes (Antibiotics; Salicylates or other drugs; Factors limiting absorption or synthesis) Initial Dosage 2.5 mg - 10 mg or up to 25 mg (rarely 50 mg) 2.5 mg - 25 mg or more (rarely up to 50 mg) 16 th May 2016 Dubix K 4

5 Anticoagulant-Induced Prothrombin Deficiency in Adults To correct excessively prolonged prothrombin times caused by oral anticoagulant therapy 2.5 to 10 mg or up to 25 mg initially is recommended. In rare instances 50 mg may be required, Frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition. If, in 12 to 48 hours after oral administration, the prothrombin time has not been shortened satisfactorily, the dose should be repeated. Hypoprothrombinemia due to other causes in adults If possible, discontinuation or reduction of the dosage of drugs interfering with coagulation mechanisms (such as salicylates, antibiotics) is suggested as an alternative to administering concurrent vitamin K. The severity of the coagulation disorder should determine whether the immediate administration of vitamin K is required in addition to discontinuation or reduction of interfering drugs. A dosage of 2.5 to 25 mg or more (rarely up to 50 mg) is recommended, the amount and route of administration depending upon the severity of the condition and response obtained. The oral route should be avoided when the clinical disorder would prevent proper absorption. Bile salts must be given with the tablets when the endogenous supply of bile to the gastrointestinal tract is deficient. 4.3 Contraindications Tranexamic acid Hypersensitivity to the active substance Active thromboembolic disease History of venous or arterial thrombosis Fibrinolytic conditions following consumption coagulopathy Severe renal impairment because of risk of accumulation History of convulsions. Mefenamic acid Hypersensitivity to mefenamic acid Inflammatory bowel disease History of gastrointestinal bleeding or perforation, related to previous NSAIDs 16 th May 2016 Dubix K 5

6 therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding). Severe heart failure, hepatic failure and renal failure (see section 4.4). Because the potential exists for cross-sensitivity to aspirin, ibuprofen, or other non-steroidal anti-inflammatory drugs, mefenamic acid must not be given to patients who have previously shown hypersensitivity reaction (e.g. asthma, bronchospasm, rhinitis, angioedema or urticaria) to these medicines. During the last trimester of pregnancy (see section 4.6). Treatment of pain after coronary artery bypass graft (CABG) surgery. Vitamin K Hypersensitivity. 4.4 Special warnings and precautions for use Tranexamic acid Caution is advised in treating those with massive haematuria from the upper urinary tract, especially in haemophiliacs, as there have been some cases of ureteric obstruction. Not to be used when disseminated intravascular coagulation is in progress. The blood levels are increased in patients with renal insufficiency. Therefore, a dose reduction is recommended (see Section 4.2, Posology and Method of Administration). In those patients requiring long term administration of tranexamic acid, such as those with hereditary angio-neurotic oedema, regular eye examinations (e.g. visual acuity, slit lamp, intraocular pressure, visual fields) and liver function tests should be performed. Patients who experience visual disturbance should be withdrawn from treatment. Patients with irregular menstrual bleeding should not use tranexamic acid until the cause of irregular bleeding has been established. If menstrual bleeding is not adequately reduced by tranexamic acid, an alternative treatment should be considered. Patients with a previous thromboembolic event and a family history of 16 th May 2016 Dubix K 6

7 thromboembolic disease (patients with thrombophilia) should use tranexamic acid only if there is a strong medical indication and under strict medical supervision. The use of tranexamic acid in cases of increased fibrinolysis due to disseminated intravascular coagulation is not recommended. Clinical experience with tranexamic acid in menorrhagic children under 15 years of age is not available. The indications and method of administration indicated above should be followed strictly: In case of haematuria of renal origin, there is a risk of mechanical anuria due to formation of a ureteral clot In renal insufficiency leading to a risk of accumulation, the dosage of tranexamic acid should be reduced according to the serum creatinine level. serum creatinine between120 and 250 μmol/l: tranexamic acid iv 10 mg/kg twice daily. serum creatinine between 250 and 500 μmol/l: tranexamic acid iv 10 mg/kg once daily (every 24 hours). serum creatinine > 500 μmol/l, tranexamic acid iv 10 mg/kg every other day (every 48 hours). Before use of tranexamic acid, risk factors of thromboembolic disease should be investigated. Tranexamic acid should be administered with care in patients receiving oral contraceptives because of the increased risk of thrombosis. Mefenamic acid Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and GI and cardiovascular risks below). Patients on prolonged therapy should be kept under regular surveillance with particular attention to liver dysfunction, rash, blood dyscrasias or development of diarrhoea. Appearance of any of these symptoms should be regarded as an indication to stop therapy immediately (see section 4.8).Use with concomitant NSAIDs including cyclo-oxygenase 2 specific inhibitors (see section 4.5). Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of 'Medication 16 th May 2016 Dubix K 7

8 Overuse Headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications. Precaution should be taken in patients suffering from dehydration and renal disease, particularly the elderly. Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (See section 4.2). Respiratory disorders: Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients Cardiovascular, Renal and Hepatic impairment: The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3). Cardiovascular and cerebrovascular effects: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for mefenamic acid. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with mefenamic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). As NSAIDs can interfere with platelet function, they should be used in caution in patients with intracranial haemorrhage and bleeding diathesis. Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI 16 th May 2016 Dubix K 8

9 events. Smoking and alcohol use are added risk factors. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for patients at risk of GI bleeding such as the elderly, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5). Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of gastro-toxicity or bleeding such as corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5). When GI bleeding or ulceration occurs in patients receiving mefenamic acid the treatment should be withdrawn. SLE and mixed connective tissue disease: In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (See section 4.8). Skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Mefenamic acid should be stopped at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Female fertility: The use of mefenamic acid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of mefenamic acid should be considered. In dysmenorrhoea and menorrhagia lack of response should alert the physician to investigate other causes. Epilepsy: Caution should be exercised when treating patients suffering from epilepsy. 16 th May 2016 Dubix K 9

10 Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. In patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance (see section 5.2). Vitamin K Warnings An immediate coagulant effect should not be expected after administration of phytonadione. Phytonadione will not counteract the anticoagulant action of heparin. When vitamin K1 is used to correct excessive anticoagulant-induced hypoprothrombinemia, anticoagulant therapy still being indicated, the patient is again faced with the clotting hazards existing prior to starting the anticoagulant therapy. Phytonadione is not a clotting agent, but overzealous therapy with vitamin K1 may restore conditions which originally permitted thromboembolic phenomena. Dosage should be kept as low as possible, and prothrombin time should be checked regularly as clinical conditions indicate. Repeated large doses of vitamin K are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. Failure to respond to vitamin K may indicate a congenital coagulation defect or that the condition being treated is unresponsive to vitamin K. Precautions General Vitamin K1 is fairly rapidly degraded by light; therefore, always protect from light. Store it in closed original carton until contents have been used. Laboratory Tests Prothrombin time should be checked regularly as clinical conditions indicate. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies of carcinogenicity or impairment of fertility have not been performed with Vitamin K. Vitamin K at concentrations up to 2000 mcg/plate with or without 16 th May 2016 Dubix K 10

11 metabolic activation, was negative in the Ames microbial mutagen test. Pediatric Use Safety and effectiveness in pediatric patients have not been established with Vitamin K. Hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, have been reported with vitamin K. Geriatric Use Clinical studies of Vitamin K 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 other drug therapy. 4.5 Interaction with other medicinal products and other forms of interaction Tranexamic acid will counteract the thrombolytic effect of fibrinolytic preparations. Mefenamic acid Concurrent therapy with other plasma protein binding drugs may necessitate a modification in dosage. Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4). Concurrent administration of mefenamic acid with oral anti-coagulant drugs requires careful prothrombin time monitoring. It is considered unsafe to take NSAIDs in combination with Warfarin or Heparin unless under direct medical supervision. Lithium: a reduction in renal lithium clearance and elevation of plasma lithium levels. Patients should be observed carefully for signs of lithium toxicity. The following interactions have been reported with NSAIDs but have not necessarily been associated with Mefenamic acid Tablets: Other analgesics including cyclooxygenase-2 selective inhibitors: avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4). Antidepressants: selective serotonin reuptake inhibitors (SSRIs): increased risk of 16 th May 2016 Dubix K 11

12 gastrointestinal bleeding (see section 4.4). Anti-hypertensives and diuretics: a reduction in antihypertensive and diuretic effect has been observed. Diuretics can increase the nephrotoxicity of NSAIDs. ACE inhibitors and angiotensin-ii receptor antagonists: a reduction in anti hypertensive effect and an increased risk of renal impairment especially in elderly patients. Patients should be adequately hydrated and the renal function assessed in the beginning and during concomitant therapy. Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations. Anti-platelet agents: increased risk of gastrointestinal ulceration or bleeding (see section 4.4). Acetylsalicylic Acid: experimental data implies that mefenamic acid interferes with the anti-platelet effect of low-dose aspirin when given concomitantly, and thus may interfere with aspirin's prophylactic treatment of cardiovascular disease. However, the limitations of this experimental data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular mefenamic acid use. Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels. Ciclosporin: the risk of nephrotoxicity of ciclosporin may be increased with NSAIDs. Corticosteroids: increased the risk of gastrointestinal ulceration or bleeding (see section 4.4). Oral hypoglycaemic agents: inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia. Methotrexate: elimination of the drug can be reduced, resulting in increased plasma levels. Mifepristone: NSAIDs should not be taken for 8-12 days after mifepristone administration, NSAIDs can reduce the effects of mifepristone. Probenecid: reduction in metabolism and elimination of NSAIDs and metabolites. Quinolone antibiotics: animal data indicates that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions. Tacrolimus: possible increased risk of nephrotoxicity when NSAIDS are given with tacrolimus. 16 th May 2016 Dubix K 12

13 Zidovudine: increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemaophiliacs receiving concurrent treatment with zidovudine and ibuprofen. Vitamin K Temporary resistance to prothrombin-depressing anticoagulants may result, especially when larger doses of phytonadione are used. If relatively large doses have been employed, it may be necessary when reinstituting anticoagulant therapy to use somewhat larger doses of the prothrombin-depressing anticoagulant, or to use one which acts on a different principle, such as heparin sodium. 4.6 Fertility, Pregnancy and lactation Tranexamic acid Pregnancy There is no evidence from animal studies that tranexamic acid has any teratogenic effect, however, the usual caution with use of drugs in pregnancy should be observed. Tranexamic acid crosses the placenta. Lactation Tranexamic acid passes into breast milk to a concentration of approximately one hundredth of the concentration in the maternal blood. An antifibrinolytic effect in the infant is unlikely. Mefenamic acid Pregnancy: Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (See section 4.3 Contraindications). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus. 16 th May 2016 Dubix K 13

14 Lactation: Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Therefore, mefenamic acid should not be taken by nursing mothers. See section 4.4 Special warnings and precautions for use regarding female fertility. Vitamin K Pregnancy Category C Animal reproduction studies have not been conducted with vitamin K. It is also not known whether vitamin K can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vitamin K should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when vitamin K is administered to a nursing woman. 4.7 Effects on ability to drive and use machines Tranexamic acid has no or negligible influence on the ability to drive and use machines. Mefenamic acid Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery. 4.8 Undesirable effects Tranexamic acid Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1,000 to <1/100), rare ( 1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Immune system disorders Very rare: Hypersensitivity reactions including anaphylaxis 16 th May 2016 Dubix K 14

15 Nervous System Disorders Very rare: Convulsions, particularly in case of misuse Eye disorders Rare: Colour vision disturbances, retinal vein/artery occlusion Vascular disorders Rare: Thromboembolic events Very rare: Arterial or venous thrombosis at any sites. Malaise with hypotension, with or without loss of consciousness (generally following a too fast intravenous injection, exceptionally after oral administration). Gastro-intestinal disorders Very rare: Digestive effects such as nausea, vomiting and diarrhoea, may occur but disappear when the dosage is reduced. Skin and subcutaneous tissue disorders Rare: Allergic skin reactions Mefenamic acid The most frequently reported side effects associated with mefenamic acid involve the gastrointestinal tract. Diarrhoea occasionally occurs following the use of mefenamic acid. Although this may occur soon after starting treatment, it may also occur after several months of continuous use. The diarrhoea has been investigated in some patients who have continued this drug in spite of its continued presence. These patients were found to have associated proctocolitis. If diarrhoea does develop the drug should be withdrawn immediately and this patient should not receive mefenamic acid again. Frequencies are not known for the following adverse reactions: Blood and the lymphatic system disorders Haemolytic anaemia (reversible when mefenamic acid is stopped), anaemia, hypoplasia bone marrow, haematocrit decreased, thrombocytopenic purpura, temporary lowering of the white blood cell count (leukopenia) with a risk of infection, sepsis, and disseminated intravascular coagulation. Agranulocytosis, aplastic anaemia, eosinophilia, neutropenia, pancytopenia, thrombocytopenia. Immune system disorders 16 th May 2016 Dubix K 15

16 Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm, or dyspnoea or (c) assorted skin disorders including rashes of various types, pruritus, urticaria, purpura, angioedema, and more rarely exfoliative or bullous dermatoses (including epidermal necrolysis and erythema multiforme). Metabolism and nutritional disorders Glucose intolerance in diabetic patients, hyponatraemia Pyschiatric disorders Confusion, depression, hallucinations, nervousness. Nervous system disorders Optic neuritis, headaches, paraesthesia, dizziness, drowsiness, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4). Blurred vision, convulsions, insomnia. Eye disorders Eye irritation, reversible loss of colour vision, visual disturbances. Ear and labyrinth disorders Ear pain, tinnitus, vertigo. Cardiac / Vascular disorders Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4). Palpitations. Hypotension. Respiratory, thoracic and mediastinal disorders Asthma, dyspnoea Gastrointestinal disorders 16 th May 2016 Dubix K 16

17 The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Elderly or debilitated patients seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Anorexia, colitis, enterocolitis, gastric ulceration with or without haemorrhage, pancreatitis, steatorrhea. Hepatobiliary disorders Borderline elevations of one or more liver function tests, cholestatic jaundice. Mild hepatotoxicity, hepatitis, hepato-renal syndrome. Skin and subcutaneous tissue disorders Angioedema, laryngeal oedema, erythema multiforme, face oedema, bullous reactions including Lyell's syndrome (toxic epidermal necrolysis) and Stevens- Johnson syndrome, perspiration, rash, photosensitivity reaction, pruritus and urticaria. Renal and urinary disorders Allergic glomerulonephritis, acute interstitial nephritis, dysuria, haematuria, nephrotic syndrome, non-oliguric renal failure (particularly in dehydration), proteinuria, renal failure including renal papillary necrosis. General disorders Fatigue, malaise, multi-organ failure, pyrexia. Investigations A positive reaction in certain tests for bile in the urine of patients receiving Mefenamic acid has been demonstrated to be due to the presence of the drug and its metabolites and not to the presence of bile. Vitamin K Severe hypersensitivity reactions, including anaphylactoid reactions and deaths have been reported following parenteral administration. The majority of these reported 16 th May 2016 Dubix K 17

18 events occurred following intravenous administration. Transient "flushing sensations" and "peculiar" sensations of taste have been observed with parenteral phytonadione, as well as rare instances of dizziness, rapid and weak pulse, profuse sweating, brief hypotension, dyspnea, and cyanosis. Hyperbilirubinemia has been observed in the newborn following administration of parenteral phytonadione. This has occurred rarely and primarily with doses above those recommended. 4.9 Overdose Tranexamic acid 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. Mefenamic acid It is important that the recommended dose is not exceeded and the regime adhered to since some reports have involved daily dosages under 3g. (a) Symptoms Symptoms include headache, nausea, vomiting epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally convulsions [Mefenamic acid has a tendency to induce tonicclonic (grand mal) convulsions in overdose]. In cases of significant poisoning acute renal failure and liver damage are possible. (b) Therapeutic measure Patients should be treated symptomatically as required Within one hour of ingestion of a potentially toxic amount activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts 16 th May 2016 Dubix K 18

19 Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins. Vitamin K The intravenous and oral LD 50 s in the mouse are approximately 1.17 g/kg and greater than g/kg, respectively. 5. Pharmacological properties 5.1 Pharmacodynamic properties Tranexamic acid is an antifibrinolytic compound which is a potent competitive inhibitor of the activation of plasminogen to plasmin. At much higher concentrations it is a non-competitive inhibitor of plasmin. The inhibitory effect of tranexamic acid in plasminogen activation by urokinase has been reported to be times and by streptokinase 6-40 times greater than that of aminocaproic acid. The antifibrinolytic activity of tranexamic acid is approximately ten times greater than that of aminocaproic acid. Mefenamic acid is non-steroidal anti-inflammatory drug (NSAID) with antiinflammatory, analgesic and antipyretic properties. Its anti-inflammatory effect was first established in the UV erythema model of inflammation. Further studies included inhibition of granulation tissue growth into subcutaneous cotton pellets in rats and carrageenin induced rat paw oedema tests. Antipyretic activity was demonstrated in yeast-induced pyresis in rats. In this model its antipyretic activity was roughly equal to that of phenylbutazone and flufenamic acid, but less than that of indomethacin. Analgesic activity was demonstrated in tests involving pain sensitivity of rats paws inflamed by brewer s yeast. Mefenamic acid was less potent than flufenamic acid in this model. Prostaglandins are implicated in a number of disease processes including inflammation, modulation of the pain response, dysmenorrhoea, menorrhagia and pyrexia. In common with most NSAIDs mefenamic acid inhibits the action of prostaglandin synthetase (cyclo-oxygenase). This results in a reduction in the rate of prostaglandin synthesis and reduced prostaglandin levels. 16 th May 2016 Dubix K 19

20 The anti-inflammatory activity of NSAIDs in the rat paw oedema test has been correlated with their ability to inhibit prostaglandin synthetase. When mefenamic acid is ranked in both these tests it falls between indomethacin and phenylbutazone and it is probable that inhibition of prostaglandin synthesis contributes to the pharmacological activity and clinical efficacy of mefenamic acid. There is also considerable evidence that the fenamates inhibit the action of prostaglandins after they have been formed. They therefore both inhibit the synthesis and response to prostaglandins. This double blockade may well be important in their mode of action. Vitamin K tablets possess the same type and degree of activity as does naturallyoccurring vitamin K, which is necessary for the production via the liver of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). The prothrombin test is sensitive to the levels of three of these four factors II, VII, and X. Vitamin K is an essential cofactor for a microsomal enzyme that catalyzes the posttranslational carboxylation of multiple, specific, peptide bound glutamic acid residues in inactive hepatic precursors of factors II, VII, IX, and X. The resulting gammacarboxyglutamic acid residues convert the precursors into active coagulation factors that are subsequently secreted by liver cells into the blood. In normal animals and humans, phytonadione is virtually devoid of pharmacodynamic activity. However, in animals and humans deficient in vitamin K, the pharmacological action of vitamin K is related to its normal physiological function; that is, to promote the hepatic biosynthesis of vitamin K-dependent clotting factors. 5.2 Pharmacokinetic properties Tranexamic acid Absorption Peak plasma tranexamic acid concentration is obtained immediately after intravenous administration (500mg). Then concentration decreases until the 6th hour. Elimination half-life is about 3 hours. Distribution Tranexamic acid administered parenterally is distributed in a two-compartment model. Tranexamic acid is delivered in the cell compartment and the cerebrospinal 16 th May 2016 Dubix K 20

21 fluid with delay. The distribution volume is about 33% of the body mass. Tranexamic acid crosses the placenta, and may reach one hundredth of the serum peak concentration in the milk of lactating women. Tranexamic acid crosses the blood brain barrier. Elimination Tranexamic acid is excreted in urine as unchanged compound. 90% of the administered dose is excreted by the kidney in the twelve first hours after administration (glomerular excretion without tubular reabsorption). Following oral administration, 1.13% and 39% of the administered dose were recovered after 3 and 24 hours respectively. Mefenamic acid Absorption and Distribution Mefenamic acid is absorbed from the gastro intestinal tract. Peak levels of 10 mg/l occur two hours after the administration of a 1g oral dose to adults. Metabolism Mefenamic acid is predominantly metabolised by cytochrome P450 enzyme CYP2C9 in the liver, first to a 3 hydroxymethyl derivative (metabolite I) and then a 3 carboxyl derivative (metabolite II). Both metabolites undergo secondary conjugation to form glucuronides. Therefore, in patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Elimination Fifty-two percent of a dose is recovered from the urine, 6% as mefenamic acid, 25% as metabolite I and 21% as metabolite II. Assay of stools over a 3-day period accounted for 10-20% of the dose chiefly as unconjugated metabolite II. The plasma levels of unconjugated mefenamic acid decline with a half life of approximately two hours. Vitamin K Oral phytonadione is adequately absorbed from the gastrointestinal tract only if bile salts are present. After absorption, phytonadione is initially concentrated in the liver, 16 th May 2016 Dubix K 21

22 but the concentration declines rapidly. Very little vitamin K accumulates in tissues. Little is known about the metabolic fate of vitamin K. Almost no free unmetabolized vitamin K appears in bile or urine. 5.3 Preclinical safety data There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of this document. Preclinical safety data does not add anything of further significance to the prescriber. 6. Pharmaceutical particulars 6.1 List of excipients Ponceau 4R 6.2 Incompatibilities None known 6.3 Shelf life 24 months 6.4 Special precautions for storage Store in a cool, dry place, protect from light. Administrative data 7. Marketing authorisation holder Strides Shasun Limited Strides House, Bilekahalli, Bannerghatta Road, Bengaluru , India 8. Toll free number for reporting Date of text 16 th May th May 2016 Dubix K 22