PRECAUTIONS: 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.

  


  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 healthcare provider immediately (see WARNINGS). 
  2. 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). 
  3. Serious Skin Reactions, including DRESS:Advise patients to stop taking tolmetin sodium capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see WARNINGS). 
  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. Fetal Toxicity:Inform pregnant women to avoid use of tolmetin sodium capsules 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 capsules 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. 

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 vitrobinding 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 Agents:In 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 ®, Uristix ®, etc.). 

Drug-Food Interactions:In a 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 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: Risk Summary:Use of NSAIDs, including tolmetin sodium capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of tolmetin sodium capsules use between about 20 and 30 weeks of gestation, and avoid tolmetin sodium capsules use at about 30 weeks of gestation and later in pregnancy (see WARNINGS: Fetal Toxicity). 

Premature Closure of Fetal Ductus Arteriosus:Use of NSAIDs, including tolmetin sodium capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. 

Oligohydramnios/Neonatal Renal Impairment:Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. 

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal 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) there revealed no evidence of teratogenesis or impaired fertility due to tolmetin. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as tolmetin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations:Fetal/Neonatal Adverse Reactions: Premature Closure of Fetal Ductus Arteriosus:Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including tolmetin sodium capsules, can cause premature closure of the fetal ductus arteriosus (see WARNINGS: Fetal Toxicity). 

Oligohydramnios/Neonatal Renal Impairment:If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If tolmetin sodium capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue tolmetin sodium capsules and follow up according to clinical practice (see WARNINGS: Fetal Toxicity). 

Data:Human Data: There are no adequate, 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. 

Premature Closure of Fetal Ductus Arteriosus:Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. 

Oligohydramnios/Neonatal Renal Impairment:Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. 

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

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, 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).