Tolmetin Sodium

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 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 ).

DOSAGE AND ADMINISTRATION 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 ). After observing the response to initial therapy with tolmetin sodium tablets, 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 1 or 2 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 a few days to a week. Progressive improvement can be anticipated during succeeding weeks of therapy. If gastrointestinal symptoms occur, tolmetin sodium tablets 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 ).

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…

CONTRAINDICATIONS 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 ).

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 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