VA Class:MS120
Tolmetin is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.
Tolmetin is used for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, and other inflammatory conditions.
The potential benefits and risks of tolmetin therapy as well as alternative therapies should be considered prior to initiating tolmetin therapy.240 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.240
Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis
Tolmetin is used in the symptomatic treatment of acute and chronic rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis.
When used in the treatment of rheumatoid arthritis or juvenile rheumatoid arthritis, tolmetin has relieved pain and stiffness; reduced swelling, tenderness, and the number of joints involved; and improved mobility, grip strength, and knee joint function. In the treatment of osteoarthritis, tolmetin has relieved pain and stiffness and improved mobility and knee joint function. Tolmetin appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. The safety and efficacy of the drug in patients who are incapacitated, largely or wholly bedridden, or confined to a wheelchair with little or no capacity for self care (Functional Class IV rheumatoid arthritis) have not been established.
Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of tolmetin in the management of rheumatoid arthritis or osteoarthritis are greater than those of placebo and about equal to those of usual dosages of salicylates, ibuprofen, indomethacin, naproxen, or phenylbutazone. The results of one study in patients with osteoarthritis suggested that tolmetin (800 mg twice daily) was more effective than naproxen (500 mg twice daily) in some measures of pain relief, although improvements in functional ability did not differ. In the treatment of juvenile rheumatoid arthritis, the anti-inflammatory and analgesic effects of tolmetin are similar to those of aspirin. In at least one patient, administration of tolmetin (23-35 mg/kg daily) has been associated with a reduction of pleural and pericardial effusion, fever, and rash associated with systemic onset of juvenile rheumatoid arthritis. Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one drug might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs. (See Cautions: Precautions and Contraindications.)
In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.203, 228 Disease-modifying antirheumatic drugs (DMARDs) (e.g., abatacept, hydroxychloroquine, leflunomide, methotrexate, rituximab, sulfasalazine, tocilizumab, tofacitinib, tumor necrosis factor [TNF; TNF-α] blocking agents) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy.228 DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs.228 NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.203, 228 (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00.)
Use of tolmetin with aspirin is not recommended by the manufacturers. There is inadequate proof that the combination is more efficacious than either drug alone. the potential for adverse reactions may be increased, and there is some evidence that aspirin alters plasma tolmetin concentrations. (See Drug Interactions: Nonsteroidal Anti-Inflammatory Agents.)
Tolmetin has been reported to be effective when used in the management of ankylosing spondylitis†, but late stages of the disease did not respond as well as did early stages. The drug has also been used with some success in the treatment of adhesive capsulitis shoulder† (frozen shoulder), radiohumeral bursitis† (tennis elbow), and local trauma† (e.g., recent sprains). In one study, tolmetin was ineffective in the management of acute gouty arthritis†.
Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease† among patients who received an NSAIA for 2 years or longer.231, 232 Similar findings have been reported from some other, but not all, observational studies.231, 232, 233, 234, 235, 236
The potential benefits and risks of tolmetin therapy as well as alternative therapies should be considered prior to initiating tolmetin therapy.240
Tolmetin sodium is administered orally. Adverse GI effects may be minimized by administering tolmetin with antacids (i.e., antacid containing aluminum and magnesium hydroxides).240
The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.240 Dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.
Dosage of tolmetin sodium is expressed in terms of tolmetin.
Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis
In the symptomatic treatment of rheumatoid arthritis or osteoarthritis, the usual initial adult dosage of tolmetin is 400 mg 3 times daily, preferably including a dose on arising and a bedtime dose. Subsequent dosage should be adjusted according to the patient's response (after 1 or 2 weeks) and tolerance. The usual effective adult dosage for the symptomatic treatment of patients with rheumatoid arthritis or osteoarthritis is 600 mg to 1.8 g daily in 3 divided doses. Dosages exceeding 1.8 g daily for adults with rheumatoid arthritis or osteoarthritis have not been studied and are not recommended by the manufacturers.
In the symptomatic treatment of juvenile rheumatoid arthritis, the usual initial dosage for children 2 years of age and older is 20 mg/kg daily in 3 or 4 divided doses. Subsequent dosage should be adjusted according to the patient's response and tolerance. The usual effective dosage is 15-30 mg/kg daily. Dosages exceeding 30 mg/kg daily have not been studied and are not recommended by the manufacturers.
Symptomatic improvement usually begins in a few days to 1 week after initiation of tolmetin therapy with progressive improvement during succeeding weeks of therapy.
For the management of ankylosing spondylitis† in adults, tolmetin dosages of 600 mg to 1.6 g daily have been administered. For the management of adhesive capsulitis shoulder† (frozen shoulder), radiohumeral bursitis† (tennis elbow), or local trauma† (e.g., recent sprains), dosages of 600 mg or 1.2 g daily have been used.
Peripheral edema, sodium retention, and hypertension have occurred in patients receiving tolmetin; less frequently, congestive heart failure has occurred in patients with marginal cardiac function.
Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500, 502, 508 Use of NSAIAs also is associated with an increased risk of heart failure.500, 508
The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.241, 248, 500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500, 501, 502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500, 502, 505, 506, 508 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500, 502, 506, 508
Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.505, 508 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).500, 508, 511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.508, 511
In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.508 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508
Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.244, 245, 246, 248, 500, 501, 502, 503, 506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)
Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.500, 504, 507, 508 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.500, 504, 508 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.500, 501, 508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508
There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.240, 502, 508
Adverse reactions to tolmetin mainly involve the GI tract; severe reactions may require discontinuing the drug. The most frequent adverse effect of tolmetin is nausea which occurs in about 11% of patients. Dyspepsia, abdominal pain or discomfort, GI distress, flatulence, diarrhea, constipation, vomiting, gastritis, anorexia, glossitis, stomatitis, and mouth ulcers or irritation may also occur. Although a causal relationship has not been directly determined, one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.
Tolmetin may reactivate latent peptic ulcer and may cause peptic ulcer in patients with no previous history of ulcers; the drug also may cause perforation. GI bleeding (sometimes severe) without obvious ulcer formation has also occurred. The manufacturers state that about 40% of patients who developed peptic ulcer while receiving tolmetin had a history of ulcer disease or also were receiving other anti-inflammatory drugs including corticosteroids.
The frequency of mild adverse GI effects with tolmetin is reported by the manufacturers to be less than that with aspirin; however, some clinical studies have shown no difference in adverse GI effects between the drugs. It is not known whether tolmetin causes less peptic ulceration than does aspirin. In one study, the amount of GI bleeding as determined by fecal blood loss following administration of 1.2 g of tolmetin daily to healthy adults was reported to be less than that following 3.9 g of aspirin daily and about the same as that following 200 mg of indomethacin daily. In another study, endoscopic examination indicated that tolmetin (2 g daily) produced more gastric and duodenal mucosal damage than placebo and more duodenal damage than ibuprofen (2.4 g daily); however, there was poor correlation between subjective symptomatology and endoscopic findings. The frequency of adverse GI effects in patients receiving a maximum of 1.8 g of tolmetin daily is reportedly similar to that of patients receiving a maximum of 2.4 g of ibuprofen daily.
Adverse GI effects may be minimized by administering tolmetin with antacids (i.e., antacid containing aluminum and magnesium hydroxides).240Close supervision of tolmetin therapy is necessary, particularly in patients with a history of upper GI disease. Tolmetin should be used in patients with GI bleeding or active peptic ulceration only when the potential benefits justify the possible risks, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving concomitant anticoagulants or corticosteroids) should be monitored closely for signs and symptoms of ulcer perforation or severe GI bleeding.
Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.200, 201, 212, 240 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.240 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up. In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.200, 201 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.240
Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.200, 201 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.200, 201 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.240 However, short-term therapy is not without risk.240 High dosages of any NSAIA probably are associated with an increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.200, 201 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.200, 201
Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors.227, 230 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status.227, 230, 237 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than patients with osteoarthritis.227, 228, 230 In addition, most spontaneous reports of fatal GI effects have been in geriatric or debilitated patients.240
For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.203, 227, 228, 229(See Misoprostol 56:28.28.) Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.203, 227, 228 In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest.227 In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.227 Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers.227, 228 Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs.228 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.238, 239 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.238, 239
The most common adverse nervous system effects of tolmetin include headache, dizziness, lightheadedness, tension or nervousness, drowsiness, and mental depression. Insomnia, mood elevation, vertigo, weakness, paresthesia, asthenia, and malaise have also been reported.
Visual disturbances have occurred during tolmetin therapy. Optic neuropathy and retinal and macular changes have occurred rarely in patients receiving tolmetin; however, a causal relationship to the drug has not been established. Clinical studies of up to 2-years' duration have shown no changes in the eye attributable to tolmetin; however, because high doses of tolmetin have caused ocular changes in rats and NSAIAs have caused adverse ocular effects in humans, the manufacturers recommend periodic ophthalmologic examinations during prolonged tolmetin therapy.
Patients receiving tolmetin have experienced tinnitus. Deterioration in hearing has been reported rarely.
Adverse hematologic effects of tolmetin include anemia and small and transient decreases in hemoglobin concentration or hematocrit not associated with GI bleeding. Leukopenia (including granulocytopenia), thrombocytopenia, and hemolytic anemia have also been reported. One case of fatal agranulocytosis has been associated with tolmetin. Tolmetin can inhibit platelet aggregation and prolong bleeding time. Patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during tolmetin therapy.
Hematuria, proteinuria, dysuria, elevations in BUN, and urinary tract infections have been reported in patients receiving tolmetin. Increases in serum uric acid concentration have also been reported. Reversible renal failure and nephrotic syndrome have been associated with tolmetin administration. In addition, acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome have also occurred. Renal biopsy findings in one patient were suggestive of an acute allergic interstitial nephritis. Chronic high doses of the drug have caused nephritis, glomerular sclerosis, and renal papillary necrosis and lesions in animals.
Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury.240
Severe hepatic reactions, including jaundice and hepatitis (which may be fatal), have been reported rarely in patients receiving tolmetin. Abnormal liver function test results including increases in serum alkaline phosphatase and AST (SGOT) concentrations have occurred in some patients receiving the drug.
Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in less than 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Tolmetin should be discontinued if signs or symptoms of a severe hepatic reaction occur. (See Cautions: Precautions and Contraindications.)
Rash, pruritus, urticaria, purpura, erythema multiforme, skin irritation, and sweating have occurred during therapy with the drug. Fever, sore throat, pharyngitis, lymphadenopathy, serum sickness, chest pain, and weight loss or gain have also occurred during tolmetin therapy. Anaphylactoid reactions following tolmetin administration occur rarely; however, they have been reported to occur at a somewhat greater frequency than following administration of other NSAIAs. Reversible aseptic meningitis occurred in one patient with systemic lupus erythematosus who received tolmetin. Epistaxis has occurred during tolmetin therapy, although a causal relationship has not been established.
Precautions and Contraindications
Patients should be advised that tolmetin, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.200, 201, 240, 500, 508 Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases, and the drugs have a major role in the management of pain.200, 201 Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.200, 201
Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.240
NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.240, 244, 245, 246, 248, 500, 502, 508 (See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.240, 500, 508 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505, 511, 512, 516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.240, 500, 508 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.240, 500, 508 Tolmetin should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if tolmetin is used in such patients, the patient should be monitored for cardiac ischemia.508
There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.240, 241, 502, 508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.240 Because of the potential for increased adverse effects, patients receiving tolmetin should be advised not to take aspirin.240
Use of NSAIAs can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.240 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.240, 508, 509 NSAIAs should be used with caution in patients with hypertension.240 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.240
Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that tolmetin should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if tolmetin is used in such patients, the patient should be monitored for worsening heart failure.508 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)
The risk of potentially serious adverse GI effects should be considered in patients receiving tolmetin, particularly in patients receiving chronic therapy with the drug.200, 201(See Cautions: GI Effects.) Tolmetin should be used with caution in patients with a history of upper GI disease. Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.204
Tolmetin should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration,204 and such patients should receive an appropriate ulcer preventive regimen.203, 227, 228, 229 All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs and symptoms of ulcer perforation or GI bleeding.240 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed.240 For patients who are at high risk, therapy other than an NSAIA should be considered.240
Elevations in serum ALT may be the most sensitive indicator of NSAIA-induced liver dysfunction. Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving tolmetin should be evaluated for evidence of the development of a severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) have been reported in patients receiving NSAIAs.240 Although such reactions are rare, tolmetin should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).
Patients receiving tolmetin are at risk of developing adverse renal effects.204Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.204 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.204, 240 Patients at greatest risk of this reaction include those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II antagonist concomitantly; and geriatric patients.204, 240, 243 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.240 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.204 Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.
Patients with impaired renal function should be monitored closely during tolmetin therapy, and dosage should be reduced if necessary, since the drug is eliminated principally by the kidneys. Tolmetin has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of tolmetin is not recommended in patients with advanced renal disease.240 If tolmetin is used in patients with severe renal impairment, close monitoring of renal function is recommended.240
Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during tolmetin therapy should have an ophthalmologic examination.240(See Cautions: Ocular and Otic Effects.)
Tolmetin is not a substitute for corticosteroid therapy.240 Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration and the drugs should be used concomitantly with caution. If corticosteroid dosage is decreased during tolmetin therapy, it should be done gradually and patients should be observed for adverse effects, including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.
Each 200 mg of tolmetin (as tolmetin sodium) contains about 0.8 mEq of sodium; this should be considered in patients whose sodium intake must be restricted.
Patients should be warned that tolmetin may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).
The possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mask the usual signs and symptoms of infection or other diseases should be considered.
Tolmetin should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy).204 If signs and/or symptoms of anemia occur during therapy with tolmetin, hemoglobin concentration or hematocrit should be determined.240
Anaphylactoid reactions have been reported in patients receiving tolmetin.204, 240 Patients receiving tolmetin should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.240
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.240 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.240 Tolmetin should be discontinued at the first appearance of rash or any other sign of hypersensitivity.240
Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1201 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1201 Symptoms may resemble those of an acute viral infection.1201 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1202 If such signs or symptoms develop, tolmetin should be discontinued and the patient evaluated immediately.1201
The manufacturers state that tolmetin is contraindicated in patients with known hypersensitivity to the drug.204 In addition, NSAIAs generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients.240 Although NSAIAs generally are contraindicated in these patients, the drugs occasionally have been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, NSAIAs should be used with caution in patients with asthma.240 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.240 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.
NSAIAs are contraindicated in the setting of CABG surgery.508
Safe use of tolmetin in children younger than 2 years of age has not been established; however, the drug has been used safely and effectively in children 2 years of age and older.
Tolmetin should be used with caution in geriatric individuals 65 years of age or older.240 Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.240
Mutagenicity and Carcinogenicity
No evidence of mutagenesis was observed with tolmetin in the Ames microbial mutagen test with metabolic activation.
No evidence of carcinogenic potential was observed in rats receiving tolmetin dosages up to 75 mg/kg daily for 24 months or in mice receiving up to 50 mg/kg daily for 18 months.
Pregnancy, Fertility, and Lactation
Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1200, 1201 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1200, 1201 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1200, 1201 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.1200, 1201
Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1200, 1201 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200, 1201 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200, 1201 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200, 1201 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1200, 1201 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1201 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1201 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1201
Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1201 In animal studies, inhibitors of prostaglandin synthesis, such as tolmetin, were associated with increased pre- and post-implantation losses.1201 Prostaglandins also have an important role in fetal kidney development.1201 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1201
Reproduction studies in rats and rabbits have not revealed evidence of teratogenic effects at tolmetin dosages up to 1.5 times the maximum recommended human dose (based on a patient weight of 60 kg).1201
The effects of tolmetin on labor and delivery are unknown.1201 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, and decreased pup survival.1201
Use of NSAIAs may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1203 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.1203 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1203
Reproduction studies in rats and rabbits have shown no impairment of fertility by tolmetin.
Tolmetin is distributed into milk. Because of the potential for adverse effects of tolmetin in neonates, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman.240
Because tolmetin is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Although no clinically important drug interactions have been reported, patients receiving tolmetin with any of these drugs should be observed for adverse effects.
Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists
There is some evidence that concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.240, 247
Anticoagulants and Thrombolytic Agents
The effects of warfarin and NSAIAs on GI bleeding are synergistic.240 Concomitant use of NSAIAs and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.240
Although the binding of warfarin to plasma proteins does not appear to be affected by tolmetin, there have been rare reports of increased prothrombin time and bleeding in patients receiving the drugs concurrently. Tolmetin does not affect prothrombin time when administered alone. Because tolmetin may cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase).
Nonsteroidal Anti-inflammatory Agents
Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.240 Because of the potential for increased adverse effects, patients receiving tolmetin should be advised not to take aspirin.240 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.240, 502, 508
Administration of aspirin with tolmetin may increase free tolmetin and decrease total tolmetin concentrations in plasma, presumably by displacing tolmetin from binding sites; increased metabolism and/or excretion of tolmetin may result. The clinical importance of this pharmacokinetic interaction has not been established.
In adults with diabetes mellitus, administration of tolmetin with insulin or the sulfonylureas does not appear to alter the clinical effects of either tolmetin or the antidiabetic agent.
NSAIAs can reduce the natriuretic effects of furosemide or thiazide diuretics.240 This effect may be related to inhibition of renal prostaglandin synthesis.240 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for signs of renal failure and for efficacy of the diuretic.240
NSAIAs appear to decrease renal clearance of lithium.240The mechanism involved in the reduction of lithium clearance by NSAIAs is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium.240If tolmetin and lithium are used concomitantly, the patient should be observed for signs and symptoms of lithium toxicity.240
The manufacturers state that tolmetin and methotrexate should be used concomitantly with caution.204Severe, sometimes fatal, toxicity has occurred following administration of an NSAIA concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis.205, 206, 207, 208, 209, 210, 211 The toxicity was associated with elevated and prolonged blood concentrations of methotrexate.205, 206, 207, 208, 209, 210, 211 The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination.204, 205, 206, 207, 208, 209, 210, 211 Further studies are needed to evaluate the interaction between NSAIAs and methotrexate.206, 207, 208, 209, 210 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.)
Concomitant use of NSAIAs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1203 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.1203 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.1203 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant NSAIA and pemetrexed therapy.1203
Tolmetin should be used cautiously, if at all, with other drugs that might potentiate the adverse GI effects.
The dicarboxylic acid metabolite of tolmetin causes a false-positive reaction for proteinuria when tests that rely on acid precipitation (e.g., sulfosalicylic acid) are used. The drug does not interfere with tests for proteinuria using dye-impregnated reagent strips (Albustix®, Uristix®).
Tolmetin does not interfere with the clinical evaluation of the immediate type hypersensitivity skin test or the tuberculin skin test, apparently because the drug does not interfere with the immune mechanisms that are measured by these skin tests.
Limited information is available on the acute toxicity of tolmetin.
In acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage, followed by administration of activated charcoal. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and symptomatic treatment should be initiated. Since tolmetin is acidic and excreted in the urine, alkalinization of the urine with sodium bicarbonate may enhance urinary tolmetin excretion. (See Pharmacokinetics: Elimination.)
Tolmetin has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated with the inhibition of prostaglandin synthesis. Tolmetin inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.221, 222, 223, 224, 225, 226 Tolmetin, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.221, 222, 223, 224, 225, 226 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.221, 222, 223, 224, 225, 226
Anti-inflammatory, Analgesic, and Antipyretic Effects
The anti-inflammatory, analgesic, and antipyretic effects of tolmetin and other NSAIAs, including selective inhibitors of COX-2 (i.e., celecoxib), appear to result from inhibition of prostaglandin synthesis. While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.221, 222, 223, 224, 225, 226
Tolmetin does not possess glucocorticoid or adrenocorticoid-stimulating properties.
Although the mechanism of the antipyretic effect of NSAIAs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.
Tolmetin has been reported to adversely affect renal function. (See Cautions: Renal Effects.) Although the mechanisms of adverse renal effects have not been determined, they may be related to inhibition of renal prostaglandin synthesis.
Tolmetin does not appear to have uricosuric activity.
Tolmetin can cause gastric mucosal damage which may result in ulceration and/or bleeding. (See Cautions: GI Effects.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.221, 222, 223, 224, 225, 226, 227 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.223, 227
Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.225 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to be determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.225
Tolmetin can inhibit platelet aggregation and may prolong bleeding time. In one study, the drug inhibited the platelet response to adenosine diphosphate and occasionally to collagen; response to the epinephrine-induced release reaction was variable. In the same study, mean bleeding time was prolonged in healthy individuals from 5.9 minutes to 12.5 minutes; bleeding time returned to baseline values after discontinuance of the drug. Similar to aspirin and other prototypical NSAIAs, the effects of tolmetin on platelets appear to be associated with inhibition of the synthesis of prostaglandins produced by COX-1.225Tolmetin does not appear to alter prothrombin time.
In all studies described in the Pharmacokinetics section, the drug was administered as the sodium salt; dosage is expressed in terms of tolmetin.
Tolmetin is rapidly and almost completely absorbed from the GI tract. When tolmetin is taken immediately after food, peak drug concentrations and areas under the plasma concentration-time curves (AUCs) are decreased compared with administration 4 hours after food. Total bioavailability and peak plasma concentrations of tolmetin were reduced by 16 and 50%, respectively, following administration of the drug immediately after food. When tolmetin is administered concomitantly with milk, no effect on peak plasma concentration of the drug has been observed, but total bioavailability has been reduced by 16%. The clinical importance of these effects has not been established. Concomitant administration of an aluminum and magnesium hydroxides antacid (Maalox®) does not appear to alter the absorption of tolmetin. Following oral administration of a single 400-mg dose of tolmetin to healthy fasting men, peak plasma drug concentrations of approximately 40 mcg/mL are reached in 30-60 minutes. Following oral administration of a single 600-mg tablet of Tolectin®, peak tolmetin plasma concentrations occurred 20 minutes later than the time to peak plasma concentrations with oral administration of a single 200-mg tablet of Tolectin®; the clinical importance of this effect has not been established.204 Plasma drug concentrations required for anti-inflammatory effect have not been determined.
The apparent volume of distribution of tolmetin in healthy men is 9.1 L. After therapeutic doses, tolmetin is approximately 99% bound to albumin. In animals, tolmetin crosses the blood-brain barrier and the placenta. Tolmetin is distributed into milk.
The plasma half-life of tolmetin has been reported to be about 1 hour in healthy men.
Tolmetin is oxidized in the liver to an inactive dicarboxylic acid metabolite.
Essentially all of the drug is excreted in the urine within 24 hours as the dicarboxylic acid metabolite (60%), unchanged tolmetin (20%), and tolmetin conjugates (20%). Results of animal studies indicate that alkalinization of the urine with sodium bicarbonate enhances urinary excretion of tolmetin. The pharmacokinetics of tolmetin appear to be similar in healthy adults and in patients with rheumatoid arthritis; however, in one study, an increase in renal clearance of the drug and its metabolites was reported in patients with rheumatoid arthritis.
Tolmetin, a pyrrole acetic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA). The drug is structurally and pharmacologically related to zomepirac. Tolmetin is commercially available as the sodium dihydrate salt; however, potency of the commercially available capsules and tablets is expressed in terms of tolmetin. Tolmetin sodium dihydrate occurs as a light yellow to light orange, crystalline powder and is freely soluble in water and slightly soluble in alcohol. The pKa of the drug is 3.5. Each 200 mg of tolmetin (as tolmetin sodium) contains about 0.8 mEq of sodium.
Tolmetin sodium capsules and tablets should be stored in tight, light-resistant containers at 15-30°C.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 400 mg (of tolmetin)* | Tolmetin Sodium Capsules | |
Tablets, film-coated | 600 mg (of tolmetin)* | Tolmetin Sodium Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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