Data from FDA - Curated by EPG Health - Last updated 29 January 2017

Indication(s)

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of tolmetin sodium capsules and other treatment options before deciding to use tolmetin sodium capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Tolmetin sodium capsules are indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. Tolmetin sodium capsules are indicated in the treatment of acute flares and the long-term management of the chronic disease. Tolmetin sodium capsules are also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of tolmetin sodium capsules have not been established in pediatric patients under 2 years of age (see PRECAUTIONS, Pediatric Use and DOSAGE AND ADMINISTRATION).

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Advisory information

contraindications
CONTRAINDICATIONS Tolmetin sodium capsules are contraindicated in patients with known hypersensitivity to tolmetin sodium. Tolmetin sodium capsules 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). Tolmetin sodium capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Special warnings and precautions
PRECAUTIONS General Tolmetin sodium capsules 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. 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 capsules have ophthalmologic evaluations. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including tolmetin sodium capsules. 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 capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), tolmetin sodium capsules should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs, including tolmetin sodium capsules. 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 capsules, 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 capsules 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 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 capsules 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. 1. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately (see WARNINGS). 2.Tolmetin sodium capsules, 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). 3.Tolmetin sodium capsules, 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 advise 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. 4. Heart Failure And Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS). 5.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. 6.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). 7.In late pregnancy, as with other NSAIDs, tolmetin sodium capsules should be avoided because they may 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 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 capsules should be discontinued. Drug Interactions 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. Aspirin As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as postmarketing 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. 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. 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. 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 capsules to patients on anticoagulants. 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 capsules 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®, Uristix®, etc.). 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%. 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. Pregnancy Teratogenic Effects Pregnancy category C Reproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the maximum clinical dose based on a body weight of 60 kg) revealed no evidence of teratogenesis or impaired fertility due to tolmetin sodium. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Tolmetin sodium capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. 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. 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. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 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
ADVERSE REACTIONS 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 non-steroidal 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. 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 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 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 Incidence Less Than 1% - (Causal Relationship Unknown) Other adverse reactions were reported less frequently than 1 in 100 in 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

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of tolmetin sodium capsules and other treatment options before deciding to use tolmetin sodium capsules. 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 capsules, 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 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 a few days to a week. Progressive improvement can be anticipated during succeeding weeks of therapy. If gastrointestinal symptoms occur, tolmetin sodium capsules can be administered with antacids other than sodium bicarbonate. Tolmetin sodium capsule 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 Interactions).
Pregnancy and lactation
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.

Interactions

Drug Interactions 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. Aspirin As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as postmarketing 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. 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. 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. 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 capsules to patients on anticoagulants. 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 capsules or the hypoglycemic agents.

More information

Category Value
Authorisation number ANDA073290
Orphan designation No
Product NDC 0093-2075
Date Last Revised 13-01-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 198296
Marketing authorisation holder Teva Pharmaceuticals USA, Inc.
Warnings Cardiovascular Thrombotic Events •Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS). •Tolmetin sodium capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS). Gastrointestinal Risk •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).