DESCRIPTION SECTION.

DESCRIPTION. Each tablet for oral administration contains 738 mg of tolmetin sodium, USP as the dihydrate in an amount equivalent to 600 mg of tolmetin. Each tablet contains 54 mg (2.35 mEq) of sodium and the following inactive ingredients: black iron oxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch, sodium lauryl sulfate, titanium dioxide, triacetin and yellow iron oxide.The pKa of tolmetin is 3.5 and tolmetin sodium is freely soluble in water.Tolmetin sodium is nonselective non-steroidal anti-inflammatory agent. The structural formula is:Sodium 1-methyl-5 p-toluoylpyrrole-2-acetate dihydrate Molecular Formula: C15H14NNaO3o2H2 M.W. 315.30. Structure Image.

LABORATORY TESTS SECTION.

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 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 should be discontinued.

NURSING MOTHERS SECTION.

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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL TOLMETIN SODIUM 600 MG TABLET. Label Image.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effectiveness in pediatric patients below the age of years have not been established.

PRECAUTIONS SECTION.

PRECAUTIONS. GeneralTolmetin 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 decision is made to discontinue corticosteroids.The pharmacological activity of tolmetin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.Opthalmological EffectsBecause 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 have ophthalmologic evaluations.Hepatic EffectsBorderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including tolmetin. 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 more severe hepatic reaction while on therapy with tolmetin. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), tolmetin should be discontinued.Hematological EffectsAnemia is sometimes seen in patients receiving NSAIDs including tolmetin. 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, 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 who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.Preexisting AsthmaPatients 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 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. 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.Tolmetin, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects). Tolmetin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. 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 signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal (GI) Effects: Risk of Ulceration, Bleeding, and Perforation). Tolmetin, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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 be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy as with other NSAIDs, tolmetin should be avoided because it will cause premature closure of the ductus arteriosus.. Tolmetin, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects). Tolmetin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. 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 signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal (GI) Effects: Risk of Ulceration, Bleeding, and Perforation). Tolmetin, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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 be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy as with other NSAIDs, tolmetin should be avoided because it will cause premature closure of the ductus arteriosus.. 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 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 should be discontinued.. Drug Interactions. ACE InhibitorsReports 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.AspirinAs with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is not generally recommended because of the potential of increased adverse effects.DiureticsClinical 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.LithiumNSAIDs have produced an elevation of plasma lithium levels and 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.MethotrexateNSAIDs 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.WarfarinThe effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have 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 and warfarin therapy. Therefore, caution should be exercised when administering tolmetin to patients on anticoagulants.Hypoglycemic AgentsIn adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either tolmetin or the hypoglycemic agents.. 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(R), Uristix(R), etc.).. Drug-Food Interactions. In controlled single-dose study, administration of tolmetin with milk had no effect on peak plasma tolmetin concentrations, but decreased total tolmetin bioavailability by 16%. When tolmetin was taken immediately after meal, peak plasma tolmetin concentrations were reduced by 50% while total bioavailability was again decreased by 16%.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Tolmetin sodium did not possess any carcinogenic liability in the following long-term studies: 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.. Pregnancy. Teratogenic EffectsPregnancy Category CReproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the maximum clinical dose based on body weight of 60 kg) revealed no evidence of teratogenesis or impaired fertility due to tolmetin. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women. Tolmetin should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.Nonteratogenic EffectsBecause of the known effects of NSAIDs on the fetal cardiovascular system (closure of the 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 tolmetin on labor and delivery in pregnant women are unknown.. 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, 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 years have not been established.. Geriatric Use. As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The adverse reactions which have been observed in clinical trials encompass observations in about 4,370 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 non-steroidal anti-inflammatory drugs and, as expected, gastrointestinal complaints were most frequent. In clinical trials with tolmetin, about 10% of patients dropped out because of adverse reactions, mostly gastrointestinal in nature.Incidence Greater Than 1%The following adverse reactions which occurred more frequently than in 100 were reported in controlled clinical trials:Gastrointestinal: nausea (11%), dyspepsia 1, gastrointestinal distress1, abdominal pain1, diarrhea1, flatulence1, vomiting1, constipation, gastritis, and peptic ulcer. Forty percent of the ulcer patients had 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 Whole: headache1, asthenia1, chest painCardiovascular: elevated blood pressure1, edema1 Central Nervous System: dizziness1, drowsiness, depressionMetabolic/Nutritional: weight gain1, weight loss1 Dermatologic: skin irritationSpecial Senses: tinnitus, visual disturbanceHematologic: Small and transient decreases in hemoglobin and hematocrit not associated with gastrointestinal bleeding have occurred. These are similar to changes reported with other non-steroidal anti-inflammatory drugs.Urogenital: elevated BUN, urinary tract infection Reactions occurring in 3% to 9% of patients treated with tolmetin sodium. Reactions occurring in fewer than 3% of the patients are unmarked.Incidence Less Than 1%(Causal Relationship Probable) The following adverse reactions were reported less frequently than in 100 in controlled clinical trials or were reported since marketing. The probability exists that there is causal relationship between tolmetin and these adverse reactions.Gastrointestinal: gastrointestinal bleeding with or without evidence of peptic ulcer, perforation, glossitis, stomatitis, hepatitis, liver function abnormalities.Body as Whole: anaphylactoid reactions, fever, lymphadenopathy, serum sicknessHematologic: hemolytic anemia, thrombocytopenia, granulocytopenia, agranulocytosisCardiovascular: congestive heart failure in patients with marginal cardiac functionDermatologic: urticaria, purpura, erythema multiforme, toxic epidermal necrolysisUrogenital: hematuria, proteinuria, dysuria, renal failureIncidence Less Than 1%(Causal Relationship Unknown) Other adverse reactions were reported less frequently than in 100 in controlled clinical trials or were reported since marketing, but causal relationship between tolmetin and the reaction could not be determined. These rarely reported reactions are being listed as alerting information for the physician since the possibility of causal relationship cannot be excluded.Body as Whole: epistaxisSpecial Senses: optic neuropathy, retinal and macular changes.

BOXED WARNING SECTION.

Cardiovascular RiskNSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI) and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). Tolmetin sodium is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS). Gastrointestinal RiskNSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS) NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI) and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS). Tolmetin sodium is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS). NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Tolmetin sodium did not possess any carcinogenic liability in the following long-term studies: 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.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Studies in animals have shown tolmetin sodium to possess anti-inflammatory, analgesic and antipyretic activity. In the rat, tolmetin prevents the development of experimentally induced polyarthritis and also decreases established inflammation.The mode of action of tolmetin is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation. Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin 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 to 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 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 biphasic elimination from the plasma consisting of rapid phase with half-life of to hours followed by slower phase with half-life of about hours. Peak plasma levels of approximately 40 mcg/mL are obtained with 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 single dose.In two fecal blood loss studies of to days duration involving 15 subjects each, tolmetin did not induce an increase in blood loss over that observed during 4-day drug free control period. In the same studies, aspirin produced greater blood loss than occurred during the drug free control period, and greater blood loss than occurred during the tolmetin sodium treatment period. In one of the two studies, indomethacin produced greater fecal blood loss than occurred during the drug free control period; in the second study, indomethacin did not induce significant increase in blood loss.Tolmetin 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 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 is as effective as aspirin in controlling disease activity, with 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 group.Tolmetin has produced additional therapeutic benefit when added to regimen of gold salts and, to lesser extent, with corticosteroids. Tolmetin 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.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Tolmetin is contraindicated in patients with known hypersensitivity to tolmetin sodium.Tolmetin 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: General: Preexisting Asthma).Tolmetin is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Carefully consider the potential benefits and risks of tolmetin 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 (see WARNINGS).After observing the response to initial therapy with tolmetin sodium, the dose and frequency should be adjusted to suit an individual patients 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 dose on arising and dose at bedtime. To achieve optimal therapeutic effect the dose should be adjusted according to the patients response after or weeks. Control is usually achieved at doses of 600 mg to 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 few days to week. Progressive improvement can be anticipated during succeeding weeks of therapy. If gastrointestinal symptoms occur, tolmetin 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 (see PRECAUTIONS: Drug-Food Interaction).

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

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(R), Uristix(R), etc.).

DRUG INTERACTIONS SECTION.

Drug Interactions. ACE InhibitorsReports 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.AspirinAs with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is not generally recommended because of the potential of increased adverse effects.DiureticsClinical 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.LithiumNSAIDs have produced an elevation of plasma lithium levels and 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.MethotrexateNSAIDs 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.WarfarinThe effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have 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 and warfarin therapy. Therefore, caution should be exercised when administering tolmetin to patients on anticoagulants.Hypoglycemic AgentsIn adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either tolmetin or the hypoglycemic agents.

GERIATRIC USE SECTION.

Geriatric Use. As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Tolmetin Sodium Tablets, USP are available containing 738 mg of tolmetin sodium, USP as the dihydrate in an amount equivalent to 600 mg of tolmetin.The tablet is beige film-coated, oval-shaped, unscored tablet debossed with 313 on one side and blank on the other side. They are available as follows:NDC 0378-0313-01bottles of 100 tabletsStore at 20 to 25C (68 to 77F). [See USP for Controlled Room Temperature.]Protect from light.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED MAY 2008TLNT:R1mc.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Carefully consider the potential benefits and risks of tolmetin sodium tablets and other treatment options before deciding to use tolmetin sodium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).Tolmetin sodium tablets are indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. Tolmetin is indicated in the treatment of acute flares and the long-term management of the chronic disease.Tolmetin is also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of tolmetin have not been established in pediatric patients under years of age (see PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION).

INFORMATION FOR PATIENTS SECTION.

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.Tolmetin, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects). Tolmetin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. 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 signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal (GI) Effects: Risk of Ulceration, Bleeding, and Perforation). Tolmetin, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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 be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy as with other NSAIDs, tolmetin should be avoided because it will cause premature closure of the ductus arteriosus.. Tolmetin, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects). Tolmetin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. 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 signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal (GI) Effects: Risk of Ulceration, Bleeding, and Perforation). Tolmetin, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., 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 be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy as with other NSAIDs, tolmetin should be avoided because it will cause premature closure of the ductus arteriosus.

LABOR & DELIVERY SECTION.

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 on labor and delivery in pregnant women are unknown.

PREGNANCY SECTION.

Pregnancy. Teratogenic EffectsPregnancy Category CReproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the maximum clinical dose based on body weight of 60 kg) revealed no evidence of teratogenesis or impaired fertility due to tolmetin. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women. Tolmetin should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.Nonteratogenic EffectsBecause of the known effects of NSAIDs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

SPL UNCLASSIFIED SECTION.

MANAGEMENT OF OVERDOSAGE. In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage followed by the administration of activated charcoal.

WARNINGS SECTION.

WARNINGS. Cardiovascular Effects Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselective NSAIDs of up to years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS: Gastrointestinal (GI) Effects: Risk of Ulceration, Bleeding and Perforation).Two large, controlled, clinical trials of COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).HypertensionNSAIDs, including tolmetin, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including tolmetin, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.Congestive Heart Failure and EdemaFluid retention and edema have been observed in some patients taking NSAIDs. Tolmetin should be used with caution in patients with fluid retention or heart failure.Gastrointestinal (GI) EffectsRisk of Ulceration, Bleeding, and PerforationNSAIDs, including tolmetin, can cause serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms in patients treated with NSAIDs. Only one in five patients who develop serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for to months, and in about 2% to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing 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 prior history of ulcer disease or gastrointestinal bleeding. Patients with prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have greater than 10-fold increased risk for developing GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. 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 in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if serious GI adverse event is suspected. This should include discontinuation of the NSAID until serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.Renal EffectsLong-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome have been reported in patients treated with tolmetin.Renal toxicity has also been seen in patients in whom renal prostaglandins have compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause dose dependent 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 NSAID therapy is usually followed by recovery to the pretreatment state.Advanced Renal DiseaseNo information is available from controlled clinical trials regarding the use of tolmetin in patients with advanced renal disease. Therefore, treatment with tolmetin is not recommended in these patients with advanced renal disease. If tolmetin therapy must be initiated, close monitoring of the patients renal function is advisable.Anaphylactoid ReactionsAs with other NSAIDs, anaphylactoid reactions may occur in patients with known prior exposure to tolmetin. Tolmetin 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: General: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.Skin ReactionsNSAIDs, including tolmetin, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.PregnancyIn late pregnancy as with other NSAIDs, tolmetin should be avoided because it may cause premature closure of the ductus arteriosus (see PRECAUTIONS: Pregnancy: Teratogenic Effects. Pregnancy Category C).