Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2685
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TOLMETIN SODIUM (Capsule)
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Carefully consider the potential benefits and risks of tolmetin sodium and other treatment options before deciding to use tolmetin sodium. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals . After observing the response to initial therapy with tolmetin sodium, the dose and frequency should be adjusted to suit an individual patient's needs. For the relief of rheumatoid arthritis or osteoarthritis, the recommended starting dose for adults is 400 mg three times daily (1200 mg daily), preferably including a dose on arising and a dose at bedtime. To achieve optimal therapeutic effect the dose should be adjusted according to the patient's response after one or two weeks. Control is usually achieved at doses of 600���1800 mg daily in divided doses (generally t.i.d.). Doses larger than 1800 mg/day have not been studied and are not recommended. For the relief of juvenile rheumatoid arthritis, the recommended starting dose for pediatric patients (2 years and older) is 20 mg/kg/day in divided doses (t.i.d. or q.i.d.). When control has been achieved, the usual dose ranges from 15 to 30 mg/kg/day. Doses higher than 30 mg/kg/day have not been studied, and, therefore, are not recommended. A therapeutic response to tolmetin sodium can be expected in a few days to a week. Progressive improvement can be anticipated during succeeding weeks of therapy. If gastrointestinal symptoms occur, tolmetin sodium can be administered with antacids other than sodium bicarbonate. Tolmetin sodium bioavailability and pharmacokinetics are not significantly affected by acute or chronic administration of magnesium and aluminum hydroxides; however, bioavailability is affected by food or milk .
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Each tolmetin sodium capsule, for oral administration, contains 492 mg of tolmetin sodium (as the dihydrate), equivalent to 400 mg of tolmetin. Each capsule contains 36 mg (1.568 mEq) of sodium and the following inactive ingredients: FD&C Red No. 3, FD&C Yellow No. 6, gelatin, magnesium stearate, pregelatinized starch, talc and titanium dioxide. Each tolmetin sodium tablet, for oral administration, contains 246 mg of tolmetin sodium (as the dihydrate), equivalent to 200 mg of tolmetin (scored for 100 mg). Each tablet contains 18 mg (0.784 mEq) of sodium and the following inactive ingredients: microcrystalline cellulose, magnesium stearate, pregelatinized starch, sodium starch glycolate and talc. The pKa of tolmetin is 3.5 and tolmetin sodium is freely soluble in water. Tolmetin sodium is a nonselective nonsteroidal anti-inflammatory agent. The structural formula is: Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate.
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Studies in animals have shown tolmetin sodium to possess anti-inflammatory, analgesic, and antipyretic activity. In the rat, tolmetin sodium prevents the development of experimentally induced polyarthritis and also decreases established inflammation. The mode of action for tolmetin sodium is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin sodium is not due to pituitary-adrenal stimulation. Tolmetin sodium inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin sodium does not appear to alter the course of the underlying disease in man. In patients with rheumatoid arthritis and in normal volunteers, tolmetin sodium is rapidly and almost completely absorbed with peak plasma levels being reached within 30���60 minutes after an oral therapeutic dose. In controlled studies, the time to reach peak tolmetin plasma concentration is approximately 20 minutes longer following administration of a 600 mg tablet, compared to an equivalent dose given as 200 mg tablets. The clinical meaningfulness of this finding, if any, is unknown. Tolmetin displays a biphasic elimination from the plasma consisting of a rapid phase with a half-life of 1 to 2 hours followed by a slower phase with a half-life of about 5 hours. Peak plasma levels of approximately 40��g/mL are obtained with a 400 mg oral dose. Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. An 18-day multiple dose study demonstrated no accumulation of tolmetin when compared with a single dose. In two fecal blood loss studies of 4 to 6 days duration involving 15 subjects each, tolmetin sodium did not induce an increase in blood loss over that observed during a 4-day drug-free control period. In the same studies, aspirin produced a greater blood loss than occurred during the drug-free control period, and a greater blood loss than occurred during the tolmetin sodium treatment period. In one of the two studies, indomethacin produced a greater fecal blood loss than occurred during the drug-free control period; in the second study, indomethacin did not induce a significant increase in blood loss. Tolmetin sodium is effective in treating both the acute flares and in the long-term management of the symptoms of rheumatoid arthritis, osteoarthritis and juvenile rheumatoid arthritis. In patients with either rheumatoid arthritis or osteoarthritis, tolmetin sodium is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetin sodium is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. Mean SGOT values, initially elevated in patients on previous aspirin therapy, remained elevated in the aspirin group and decreased in the tolmetin sodium group. Tolmetin sodium has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin sodium should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased.
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Tolmetin sodium capsules are supplied as follows: Tolmetin sodium capsules equivalent to 400 mg tolmetin, orange/orange imprinted: Bottles of 100 NDC 53489-507-01Bottles of 250 NDC 53489-507-03Bottles of 500 NDC 53489-507-05Bottles of 1000 NDC 53489-507-10 Tolmetin sodium tablets equivalent to 200 mg tolmetin, off white, round scored, debossed: MP 50 Bottles of 50 NDC 53489-506-02Bottles of 90 NDC 53489-506-90Bottles of 100 NDC 53489-506-01Bottles of 250 NDC 53489-506-03Bottles of 500 NDC 53489-506-05Bottles of 1000 NDC 53489-506-10 Store at 20��to 25��C (68��to 77��F).[See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
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Cardiovascular Risk:<br/>Gastrointestinal Risk:
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General: Tolmetin sodium 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. The pharmacological activity of tolmetin sodium in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.<br/>Ophthalmological Effects: Because of ocular changes observed in animals and of reports of adverse eye findings with NSAIDs, it is recommended that patients who develop visual disturbances during treatment with tolmetin sodium have ophthalmologic evaluations.<br/>Hepatic Effects: Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including tolmetin sodium. 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 tolmetin sodium. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), tolmetin sodium should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, including tolmetin sodium. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including tolmetin sodium, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. 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, of shorter duration, and reversible. Patients receiving tolmetin sodium who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.<br/>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 NSAIDs has been reported in such aspirin-sensitive patients, tolmetin sodium should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patientswith preexisting asthma.<br/>Information for Patients: Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. 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 tests persist or worsen, tolmetin sodium should be discontinued.<br/>Drug Interactions:<br/>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.<br/>Aspirin: As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is not generally recommended because of the potential of increased adverse effects.<br/>Diuretics: 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 with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.<br/>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.<br/>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.<br/>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. The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant tolmetin sodium and warfarin therapy. Therefore, caution should be exercised when administering tolmetin sodium to patients on anticoagulants.<br/>Hypoglycemic Agents: In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either tolmetin sodium or the hypoglycemic agents.<br/>Drug/Laboratory Test Interactions: The metabolites of tolmetin sodium in urine have been found to give positive tests for proteinuria using tests which rely on acid precipitation as their endpoint (e.g., sulfosalicylic acid). No interference is seen in the tests for proteinuria using dye-impregnated commercially available reagent strips (e.g., Albustix, Uristix, etc.).<br/>Drug-Food Interactions: In a controlled single-dose study, administration of tolmetin sodium with milk had no effect on peak plasma tolmetin concentrations, but decreased total tolmetin bioavailability by 16%. When tolmetin sodium was taken immediately after a meal, peak plasma tolmetin concentrations were reduced by 50% while total bioavailability was again decreased by 16%.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Tolmetin sodium did not possess any carcinogenic liability in the following long-term studies: a 24-month study in rats at doses as high as 75 mg/kg/day, and an 18-month study in mice at doses as high as 50 mg/kg/day. No mutagenic potential of tolmetin sodium was found in the Ames Salmonella-Microsomal Activation Test. Reproductive studies revealed no impairment of fertility in animals. Effects on parturition have been shown, however, as with other prostaglandin inhibitors. This information is detailed in the Pregnancy section.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.<br/>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 tolmetin sodium on labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: Tolmetin sodium has been shown to be secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tolmetin sodium, 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.<br/>Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 have not been established.<br/>Geriatric Use: As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
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tolmetin sodium
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TOLMETIN SODIUM (Capsule)
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The adverse reactions which have been observed in clinical trials encompass observations in about 4370 patients treated with tolmetin sodium, over 800 of whom have undergone at least one year of therapy. These adverse reactions, reported below by body system, are among those typical of nonsteroidal anti-inflammatory drugs and, as expected, gastrointestinal complaints were most frequent. In clinical trials with tolmetin sodium, about 10%of patients dropped out because of adverse reactions, mostly gastrointestinal in nature.<br/>Incidence Greater Than 1%: The following adverse reactions which occurred more frequently than 1 in 100 were reported in controlled clinical trials. Gastrointestinal: Nausea (11%), dyspepsia,gastrointestinal distress,abdominal pain,diarrhea,flatulence,vomiting,constipation, gastritis, and peptic ulcer. Forty percent of the ulcer patients had a prior history of peptic ulcer disease and/or were receiving concomitant anti-inflammatory drugs including corticosteroids, which are known to produce peptic ulceration. Body as a Whole: Headache,asthenia,chest pain Cardiovascular: Elevated blood pressure,edema Central Nervous System: Dizziness,drowsiness, depression Metabolic/Nutritional: Weight gain,weight loss Dermatologic: Skin irritation Special Senses: Tinnitus, visual disturbance Hematologic: Small and transient decreases in hemoglobin and hematocrit not associated with gastrointestinal bleeding have occurred. These are similar to changes reported with other nonsteroidal anti-inflammatory drugs. Urogenital: Elevated BUN, urinary tract infection<br/>Incidence Less Than 1%: (Causal Relationship Probable) The following adverse reactions were reported less frequently than 1 in 100 controlled clinical trials or were reported since marketing. The probability exists that there is a causal relationship between tolmetin sodium and these adverse reactions. Gastrointestinal: Gastrointestinal bleeding with or without evidence of peptic ulcer, perforation, glossitis, stomatitis, hepatitis, liver function abnormalities Body as a Whole: Anaphylactoid reactions, fever, lymphadenopathy, serum sickness Hematologic: Hemolytic anemia, thrombocytopenia, granulocytopenia, agranulocytosis Cardiovascular: Congestive heart failure in patients with marginal cardiac function Dermatologic: Urticaria, purpura, erythema multiforme, toxic epidermal necrolysis Urogenital: Hematuria, proteinuria, dysuria, renal failure<br/>Incidence Less Than 1%: (Causal Relationship Unknown) Other adverse reactions were reported less frequently than 1 in 100 controlled clinical trials or were reported since marketing, but a causal relationship between tolmetin sodium and the reaction could not be determined. These rarely reported reactions are being listed as alerting information for the physician since the possibility of a causal relationship cannot be excluded. Body as a Whole: Epistaxis Special Senses: Optic neuropathy, retinal and macular changes
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Carefully consider the potential benefits and risks of tolmetin sodium and other treatment options before deciding to use tolmetin sodium. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals . Tolmetin sodium is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. Tolmetin sodium is indicated in the treatment of acute flares and the long-term management of the chronic disease. Tolmetin sodium is also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of tolmetin sodium have not been established in pediatric patients under 2 years of age .
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TOLMETIN SODIUM
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