Tranexamic Acid

Tranexamic acid is an antifibrinolytic agent which competitively inhibits the activation of plasminogen to plasmin. The drug has affinity for the five lysine-binding sites of plasminogen. It thus promotes clot stability, and is useful as adjunctive therapy in haemophilia and some other bleeding disorders.

Dose:

3 - 4 GMS IN DEVIDED DOSES PER DAY ORALLY. CHILDREN : 25 MG / KG TDS I.V. DOSE : ADULT - 4 -5 GM I.V. OVER A PERIOD OF ONE HR., THEN THE DOSE IS 1 GM EVERY HRLY IN VEIN UPTO 8 HRS. CHILDREN - 100 MG / KG, THEN 33.3 MG / KG EVERY HRLY.

Monography

Tranexamic acid Tranexamic acid (marketed in the UK under the trade name of "Cyclokapron") is an antifibrinolytic agent which competitively inhibits the activation of plasminogen to plasmin. The drug has affinity for the five lysine-binding sites of plasminogen. It thus promotes clot stability, and is useful as adjunctive therapy in haemophilia and some other bleeding disorders. The use of tranexamic acid has superseded the use of amino caproic acid, which not only has a shorter plasma half-life but is less potent and more toxic. Trials several decades ago established that regular treatment with tranexamic acid alone is of no value in prevention of haemarthroses in haemophilia. It is particularly valuable in controlling bleeding in the mouth in haemophilia and von Willebrand's disease, such as in association with dental surgery. It may also be used to control menorrhagia and epistaxis in von Willebrand's disease. Tranexamic acid is also of use in factor XI deficiency, and its use to cover dental, gynaecological or urological surgery in factor XI-deficient patients may obviate the need for replacement therapy with concentrate or plasma.It should not be used to control haematuria in severe haemophilia, as treatment may precipitate clot colic and even obstruction of the outflow from the urinary pelvis. Similarly, we do not use the drug in the setting of thoracic or abdominal surgery, as this may result in the development of insoluble haematomas. Tranexamic acid may be given alone or together with standard doses of coagulation factor concentrate. However, it should not be given to patients with inhibitory antibodies receiving activated prothrombin factor concentrates (such as FEIBA or Autoplex) as this may provoke thromboembolism. If treatment with both agents is deemed to be necessary, it is recommended that at least six hours should elapse between the last dose of APCC and the administration of tranexamic acid. By contrast, tranexamic acid may be usefully used in combination with recombinant factor VIIa to enhance haemostasis. Tranexamic acid is usually given in tablet form at a typical dose of 3 or 4 grams (in divided doses) daily for an adult. Gastrointestinal upset (nausea, vomiting and diarrhoea) may rarely occur as a side-effect, but these symptoms usually resolve if the dosage is reduced. It may also be given by intravenous injection, but it must be infused slowly as rapid injection may result in dizziness and hypotension. A syrup formulation is also available for paediatric use: the syrup contains 500mg tranexamic acid in each 5ml, and the usual dose for children is 25 mg/kg up to three times daily. The drug may be of particular use in controlling oral bleeding associated with eruption of teeth.The drug is excreted by the kidneys, and the dose must be reduced if there is renal impairment in order to avoid toxic accumulation. Antifibrinolytic (an-tee-fye-bri-noh-LIT-ik) agents are used to treat serious bleeding, especially when the bleeding occurs after dental surgery (particularly in patients with hemophilia) or certain other kinds of surgery. These medicines are also sometimes given before an operation to prevent serious bleeding in patients with medical problems that increase the chance of serious bleeding. Antifibrinolytic agents may also be used for other conditions as determined by your doctor. Antifibrinolytic agents are available only with your doctor's prescription, in the following dosage forms: Oral * Aminocaproic acid o Syrup (U.S. and Canada) o Tablets (U.S. and Canada) * Tranexamic acid o Tablets (U.S. and Canada) Parenteral * Aminocaproic acid o Injection (U.S. and Canada) * Tranexamic acid o Injection (U.S. and Canada) Before Using This Medicine In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For antifibrinolytic agents, the following should be considered: Allergies-Tell your doctor if you have ever had any unusual or allergic reaction to aminocaproic acid or tranexamic acid. Also tell your health care professional if you are allergic to any other substances, such as foods, preservatives, or dyes. Pregnancy-Studies on birth defects have not been done in humans. However, these medicines have been given to pregnant women without causing birth defects or other problems. Studies on effects of aminocaproic acid in pregnancy have not been done in animals. Tranexamic acid has not been shown to cause birth defects or other problems in animal studies. Breast-feeding-These medicines have not been reported to cause problems in nursing babies. However, small amounts of tranexamic acid pass into the breast milk. Children-Although there is no specific information comparing use of aminocaproic acid or tranexamic acid in children with use in other age groups, these medicines are not expected to cause different side effects or problems in children than they do in adults. Older adults- * For aminocaproic acid : Although there is no specific information comparing use of aminocaproic acid in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults. * For tranexamic acid : Tranexamic acid has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults. Other medicines-Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your health care professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine. Other medical problems-The presence of other medical problems may affect the use of antifibrinolytic agents. Make sure you tell your doctor if you have any other medical problems, especially: * Blood clots or a history of medical problems caused by blood clots or * Blood in the urine or * Color vision problems or * Heart disease or * Kidney disease or * Liver disease-The chance of side effects may be increased Proper Use of This Medicine Take this medicine only as directed by your doctor . Do not take more or less of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of unwanted effects. Dosing-The dose of these medicines will be different for different patients. Follow your doctor's orders or the directions on the label . The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so. For aminocaproic acid * To prevent or treat serious bleeding: o For oral dosage forms (syrup or tablets): * Adults-For the first hour, the dose is 5 grams. Then the dose is 1 or 1.25 grams per hour for eight hours. * Children-Dose is based on body weight or size and must be determined by your doctor. For the first hour, the dose is usually 100 milligrams (mg) per kilogram (kg) (45.4 mg per pound) of body weight. Then the dose is 33.3 mg per kg (15.1 mg per pound) of body weight per hour. o For injection dosage form: * Adults-At first, the dose is 4 to 5 grams injected into a vein, over a period of one hour. Then the dose is 1 gram per hour, injected into a vein over a period of eight hours. * Children-Dose is based on body weight or size and must be determined by your doctor. At first, the dose is usually 100 mg per kg (45.4 mg per pound) of body weight, injected into a vein over a period of one hour. Then the dose is 33.3 mg per kg (15.1 mg per pound) of body weight per hour, injected into a vein. For tranexamic acid * To prevent or treat serious bleeding after dental surgery: o For oral dosage form (tablets): * Adults and children-Dose is based on body weight and must be determined by your doctor. The dose is usually 25 milligrams (mg) per kilogram (kg) (11.4 mg per pound) of body weight every six to eight hours, beginning one day before surgery. After surgery, the dose is usually 25 mg per kg (11.4 mg per pound) of body weight every six to eight hours for seven to ten days. o For injection dosage form: * Adults and children-Dose is based on body weight and must be determined by your doctor. The dose is usually 10 mg per kg (4.5 mg per pound) of body weight, injected into a vein just before surgery. After surgery, the dose is usually 10 mg per kg (4.5 mg per pound) of body weight, injected into a vein every six to eight hours for seven to ten days. Missed dose- * For aminocaproic acid (e.g., Amicar): If you miss a dose, take it as soon as possible. However, if you do not remember until it is almost time for your next dose, double the next dose. Then go back to your regular dosing schedule. * For tranexamic acid (e.g., Cyklokapron): If you miss a dose, take it as soon as possible. Then take any remaining doses for the day at regularly spaced times. Do not double doses. If you have any questions about this, check with your doctor. Storage-To store this medicine: * Keep out of the reach of children. * Store away from heat and direct light. * Do not store the tablet form of this medicine in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down. * Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of the reach of children. Precautions While Using This Medicine If you will be taking tranexamic acid for longer than several days, your doctor may want you to have your eyes checked regularly by an ophthalmologist (eye doctor). This will allow your doctor to check for unwanted effects that may be caused by this medicine. If you are using aminocaproic acid syrup as a mouth rinse to control oral bleeding, and you are in the first or second trimester of pregnancy, you should spit out the syrup after rinsing without swallowing it. Side Effects of This Medicine Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. The same effect that makes aminocaproic acid or tranexamic acid help prevent or stop bleeding also may cause blood clots that could be dangerous. Check with your doctor immediately if any of the following possible signs and symptoms of blood clots occur: Less common or rare Headache (severe and sudden); loss of coordination (sudden); pains in chest, groin, or legs, especially the calves; shortness of breath (sudden); slurred speech (sudden); vision changes (sudden); weakness or numbness in arm or leg Also, check with your doctor as soon as possible if any of the following side effects occur: Less common or rare For aminocaproic acid Dizziness; headache; muscle pain or weakness (severe and continuing); ringing or buzzing in ears; skin rash; slow or irregular heartbeat-with the injection only; stomach cramps or pain; stuffy nose; sudden decrease in amount of urine; swelling of face, feet, or lower legs; unusual tiredness or weakness; weight gain (rapid) For tranexamic acid Blurred vision or other changes in vision; dizziness or lightheadedness; unusual tiredness or weakness Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome: Diarrhea; dry ejaculation; nausea or vomiting; unusual menstrual discomfort; watery eyes Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

Mefenamic Acid

MEFANAMIC ADIC IS A NSAIDS THAT EXHIBITS ANTI-INFLAMMATORY, ANALGESIC, AND ANTIPYRETIC ACTIVITIES IN ANIMAL MODELS. THE MECHANISM OF ACTION OF MEFANAMIC IS BELIEVED TO BE DUE TO INHIBITION OF PROSTAGLANDIN SYNTHESIS, PRIMARILY VIA INHIBITION OF CYCLOOXYGENASE-2 (COX-2), AND AT THERAPEUTIC CONCENTRATION IN HUMANS, IT DOES NOT INHIBITS THE CYCLOOXYGENASE-1 (COX-1) ISOENZYME.

Dose :

THE USUAL ADULT DOSE :- 500 MG THREE TIMES DAILY. CHILDREN :- 25 MG/KG/BODY WT. DAILY IN DIVIDED DOSES.

Monograph

MEFENAMIC ACID DESCRIPTION Ponstanr (mefenamic acid) is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each blue-banded, ivory capsule contains 250 mg of mefenamic acid for oral administration. Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230ø-231øC and water solubility of 0.004% at pH 7.1. The chemical name is 2-{(2,3-dimethylphenyl) amino-N-2,3-xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C 15 H 15 NO 2 . CLINICAL PHARMACOLOGY Pharmacodynamics Ponstan is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Ponstan, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics Absorption: Mefenamic acid is rapidly absorbed after oral administration. In two 500-mg single oral dose studies, the mean extent of absorption was 30.5 mcg/hr/mL (17%CV). 1,2 The bioavailability of the capsule relative to an IV dose or an oral solution has not been studied. Following a single 1-gram oral dose, mean peak plasma levels ranging from 10-20 mcg/mL 3 have been reported. Peak plasma levels are attained in 2 to 4 hours and the elimination half-life approximates 2 hours. Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. In a multiple dose trial of normal adult subjects (n=6) receiving 1-gram doses of mefenamic acid four times daily, steady-state concentrations of 20 mcg/mL were reached on the second day of administration, consistent with the short half-life. The effect of food on the rate and extent of absorption of mefenamic acid has not been studied. Concomitant ingestion of antacids containing magnesium hydroxide has been shown to significantly increase the rate and extent of mefenamic acid absorption (see PRECAUTIONS , Drug Interactions ). 1 Distribution Mefenamic acid has been reported as being greater than 90% bound to albumin. 9 The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vz ss /F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg. 2 Based on its physical and chemical properties, Ponstan is expected to be excreted in human breast milk. Metabolism: Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite I). Further oxidation to a 3-carboxymefenamic acid (Metabolite II) may occur. 10 The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. A peak plasma level approximating 20 mcg/mL was observed at 3 hours for the hydroxy metabolite and its glucuronide (n=6) after a single 1-gram dose. Similarly, a peak plasma level of 8 mcg/mL was observed at 6-8 hours for the carboxy metabolite and its glucuronide. 3 Excretion Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3-carboxymefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid. 3 The elimination half-life of mefenamic acid is approximately two hours. Half-lives of metabolites I and II have not been precisely reported, but appear to be longer than the parent compound. 3 The metabolites may accumulate in patients with renal or hepatic failure. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. Because both renal and hepatic excretion are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Ponstan should not be administered to patients with preexisting renal disease or in patients with significantly impaired renal function. TABLE 1. Pharmacokinetic Parameter Estimates for Mefenamic Acid PK Parameters Normal Healthy Adults (18-45 yr) ValueCV Tmax(hr) 2 66 Oral clearance (L/hr) 21.23 38 Apparent volume of distribution; Vz/F (L/kg) 1.06 60 Half-life; t 1 / 2 (hrs) 2 to 4 NA Special Populations Pediatric Ponstan has not been adequately investigated in pediatric patients less than 14 years of age. A study in 17 preterm infants administered 2 mg/kg indicated that the half-life was about five times as long as adults, consistent with the low activity of metabolic enzymes in newborn infants. The mean Cmax in this study was 4 mcg/mL (range 2.9-6.1). The mean time to maximum concentration (Tmax) was 8 hours (range 2-18 hrs). 11 Race: Pharmacokinetic differences due to race have not been identified. Hepatic Insufficiency: Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction. As hepatic metabolism is a significant pathway of mefenamic acid elimination, patients with acute and chronic hepatic disease may require reduced doses of Ponstan compared to patients with normal hepatic function. Renal Insufficiency: Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency. Given that mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys, the potential exists for mefenamic acid metabolites to accumulate. Ponstan should not be administered to patients with preexisting renal disease or in patients with significantly impaired renal function. Clinical Studies In controlled, double-blind, clinical trials, Ponstan was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either Ponstan, 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Ponstan was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated. INDICATIONS AND USAGE Ponstan is indicated: For relief of mild to moderate pain in patients >/=14 years of age, when therapy will not exceed one week (7 days). For treatment of primary dysmenorrhea. CONTRAINDICATIONS Ponstan is contraindicated in patients with known hypersensitivity to mefenamic acid. Ponstan should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS -- Anaphylactoid Reactions , and PRECAUTIONS -- Preexisting Asthma ). Ponstan is contraindicated in patients with active ulceration or chronic inflammation of either the upper or lower gastrointestinal tract. Ponstan should not be used in patients with preexisting renal disease. WARNINGS 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 non-steroidal 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. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. 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. Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other cotherapies or comorbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Ponstan. Ponstan should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS -- Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Advanced Renal Disease In cases with preexisting advanced kidney disease, treatment with Ponstan is not recommended (see CONTRAINDICATIONS ). Pregnancy In late pregnancy, as with other NSAIDs, Ponstan should be avoided because it may cause premature closure of the ductus arteriosus. PRECAUTIONS General Ponstan 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 Ponstan reduces inflammation, it may diminish the diagnostic signs for detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver function tests may occur in up to 15% of patients taking NSAIDs, including Ponstan. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. 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. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Ponstan. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), Ponstan should be discontinued. Renal Effects Caution should be used when initiating treatment with Ponstan in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Ponstan. Ponstan is not recommended in patients with pre-existing kidney disease (see CONTRAINDICATIONS ). Long-term administration of Ponstan has resulted in renal papillary necrosis and other renal medullary changes. Renal toxicity has also been seen in patients in which renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependant reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. 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. Ponstan 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 Ponstan. This may be due to fluid retention, GI loss, or an effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Ponstan, 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 responses 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. Ponstan does not generally affect platelet counts, or partial thromboplastin time (PTT), but may prolong prothrombin time (PT). Patients receiving Ponstan who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Fluid Retention and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Therefore, as with other NSAIDs, Ponstan should be used with caution in patients with fluid retention, hypertension, or heart failure. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Ponstan should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Information for Patients Ponstan, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNING , Risk of Gastrointestinal Ulceration, Bleeding and Perforation ). Patients should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain, or edema. Patients should be informed of the warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS ). In late pregnancy, as with other NSAIDs, Ponstan should be avoided because it may cause premature closure of the ductus arteriosus. NSAIDs are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which are less serious. Physicians may wish to discuss with their patients the potential risks (see WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS sections) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician. 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 (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Ponstan should be discontinued. Drug Interactions Aspirin As with other NSAIDs, concomitant administration of Ponstan and aspirin is not generally recommended because of the potential of increased adverse effects. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Furosemide Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy of Ponstan with furosemide, the patient should be observed closely for signs of renal failure (see PRECAUTIONS , Renal Effects ), as well as to assure diuretic efficacy. Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. Antacids: In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. 1 A number of compounds are inhibitors of CYP2C9 including fluconazole, lovastatin and trimethoprim. Drug interaction studies of mefenamic acid of these compounds have not been conducted. The possibility of altered safety and efficacy should be considered when Ponstan is used concomitantly with these drugs. Drug/Laboratory Test Interactions Ponstan may prolong prothrombin time. 4 Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary. A false-positive reaction for urinary bile, using the diazo tablet test, may result after mefenamic acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed. 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 nor in dogs at up to 10 times the human dose. 4 However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Ponstan 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 Ponstan on labor and delivery in pregnant women are unknown. Nursing Mothers Trace amounts of Ponstan may be present in breast milk and transmitted to the nursing infant. 7 Because of the potential for serious adverse reactions in nursing infants from Ponstan, 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. Pediatric Use Safety and effectiveness in pediatric patients below the age of 14 have not been established. Geriatric Use As with any NSAID, caution should be exercised in treating the elderly (65 years and older). ADVERSE REACTIONS In patients taking Ponstan or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% of patients are: Gastrointestinal experiences including--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, headaches, increased bleeding time, pruritus, rashes, tinnitus Additional adverse experiences reported occasionally and listed here by body system include: 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, leukopenia, 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 are: Body as a whole--anphylactoid 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 necrosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria Special senses--conjunctivitis, hearing impairment OVERDOSAGE Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. DOSAGE AND ADMINISTRATION As with other NSAIDs, the lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy with Ponstan, the dose and frequency should be adjusted to suit an individual patient' needs. Administration is by the oral route, preferably with food. For relief of acute pain in adults and adolescents >/=14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week. 4 For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, starting with the onset of bleeding and associated symptoms. Clinical studies indicate that effective treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days. 5