Tolmetin Sodium

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 sodium tablets are indicated in the treatment of acute flares and the long-term management of the chronic disease. Tolmetin sodium tablets are also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of tolmetin have not been established in pediatric patients under 2 years of age (see PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION ).

Tolmetin sodium tablets are 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 in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as tolmetin, increases the risk of serious gastrointestinal (GI) events [see WARNINGS ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up. Avoid the use of tolmetin in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If tolmetin is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, 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. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of tolmetin may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see PRECAUTIONS: DRUG INTERACTIONS ]. Avoid the use of tolmetin in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If tolmetin is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Gastrointestinal (GI) Effects Risk of Ulceration, Bleeding, and Perforation NSAIDs, 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 a 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 3 to 6 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 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. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a 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 a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-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 a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a 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 Disease No 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 patient's renal function is advisable. […]

General Tolmetin 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 in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Opthalmological 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 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. 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. 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 Effects Anemia 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 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 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. 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 healthcare provider immediately [see WARNINGS ]. 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 ). Serious Skin Reactions , including DRESS Advise patients to stop taking tolmetin sodium tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings ]. 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 ]. 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 ). Fetal Toxicity: Inform pregnant women to avoid use of tolmetin sodium tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with tolmetin sodium tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS; Fetal Toxicity , PRECAUTIONS; Pregnancy ]. 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 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 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. 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. […]

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 nonsteroidal 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 1 in 100 were reported in controlled clinical trials: Gastrointestinal: nausea (11%), dyspepsia * , gastrointestinal distress * , abdominal pain * , diarrhea 1 * , 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 in controlled clinical trials or were reported since marketing. The probability exists that there is a 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 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, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS) , toxic epidermal necrolysis, and fixed drug eruption (FDE) 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 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