Tolmetin

Class: Other Nonsteroidal Anti-inflammatory Agents
VA Class: MS120
Chemical Name: Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate
CAS Number: 64490-92-2

Medically reviewed by Drugs.com. Last updated on Nov 9, 2020.

• Overview
• Side Effects
• Dosage
• Professional
• Interactions
• More

Introduction

Prototypical NSAIA; pyrrole acetic acid derivative. ^a

Uses for Tolmetin

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Consider potential benefits and risks of tolmetin therapy as well as alternative therapies before initiating therapy with the drug.²⁴⁰ Use lowest possible effective dosage and shortest duration of therapy consistent with patient's treatment goals.²⁴⁰

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis.²⁴⁰

Management of juvenile rheumatoid arthritis in children ≥2 years of age.²⁴⁰

Has been reported to be effective in the management of ankylosing spondylitis† (late stages did not respond as well as early stages); 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).^a

Tolmetin Dosage and Administration

General

• Consider potential benefits and risks of tolmetin therapy as well as alternative therapies before initiating therapy with the drug.²⁴⁰

Administration

Oral Administration

Administer orally 3 or 4 times daily.²⁴⁰

Administration with antacids (i.e., antacid containing aluminum and magnesium hydroxides) may minimize adverse GI effects.²⁴⁰

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as tolmetin sodium; dosage expressed in terms of tolmetin.²⁴⁰

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.²⁴⁰ Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.²⁴⁰

Pediatric Patients

Inflammatory Diseases

Juvenile Rheumatoid Arthritis

Oral

Children ≥2 years of age: Initially, 20 mg/kg daily in 3 or 4 divided doses.²⁴⁰ Adjust dosage based on response and tolerance.²⁴⁰

Usual effective dosage: 15–30 mg/kg daily.²⁴⁰

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Initially, 400 mg 3 times daily, preferably including a dose on arising and at bedtime.²⁴⁰ Adjust dosage based on response (after 1 or 2 weeks) and tolerance.^a

Usual effective dosage: 600 mg to 1.8 g daily in 3 divided doses.²⁴⁰

Ankylosing Spondylitis†

Oral

600 mg to 1.6 g daily in divided dose has been used.^a

Adhesive Capsulitis Shoulder† (frozen shoulder), Radiohumeral Bursitis† (tennis elbow), Local Trauma† (e.g., recent sprains)

Oral

>600 mg or 1.2 g daily in divided doses has been used.^a

Prescribing Limits

Pediatric Patients

Inflammatory Diseases

Juvenile Rheumatoid Arthritis

Oral

Dosages >30 mg/kg daily have not been studied and are not recommended.²⁴⁰

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Dosages >1.8 g daily have not been studied and are not recommended.²⁴⁰

Special Populations

Renal Impairment

Reduce dosage if necessary.²⁴⁰

Geriatric Patients

Select dosage with caution (potential for age-related renal function decline).²⁴⁷

Cautions for Tolmetin

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Known hypersensitivity to tolmetin or any ingredient in the formulation.²⁴⁰

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.²⁴⁰

• In the setting of CABG surgery.⁵⁰⁸

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.^{500 502 508}

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information^{500 501 502} indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but 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}

Increased 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}

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.⁵⁰⁸

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{505 508}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;^{500 508 511} absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.^{508 511}

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.^{244 245 246 248 500 501 502 503 506} FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dose for the shortest duration necessary.^{240 500 508}

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.^{505 511 512 516} Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.⁵⁰⁸ Contraindicated in the setting of CABG surgery.⁵⁰⁸

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{240 502 508} (See Specific Drugs and Laboratory Tests under Interactions.)

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.^{200 201 212 240 227 230 237}

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{203 227 228 229} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{203 227 228} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).²²⁸

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.²⁴⁰ Use with caution in patients with hypertension; monitor BP.²⁴⁰

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.^{240 508 509} (See Specific Drugs and Laboratory Tests under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.^{240 508}

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.^{500 501 504 507 508}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.⁵⁰⁸ (See Specific Drugs and Laboratory Tests under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.⁵⁰⁸

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.²⁴⁰

Potential for overt renal decompensation.^{204 240} Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{204 240 243 247} (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported. ²⁴⁰

Immediate medical intervention and discontinuance for anaphylaxis.²⁴⁰

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.²⁴⁰

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.²⁴⁰ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).²⁴⁰

General Precautions

Ocular and Otic Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.²⁴⁰

Tinnitus reported; deterioration in hearing reported rarely.^a

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs. ²⁴⁰

Elevations of serum ALT or AST reported.²⁴⁰ Elevations of serum alkaline phosphatase also reported.^a

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.²⁴⁰ Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.²⁴⁰

Hematologic Effects

Anemia reported rarely.²⁴⁰ Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.²⁴⁰

Small and transient decreases in hemoglobin concentration or hematocrit (not associated with GI bleeding), leukopenia (including granulocytopenia), thrombocytopenia, and hemolytic anemia reported.^a One case of fatal agranulocytosis reported. ^a

May inhibit platelet aggregation and prolong bleeding time.²⁴⁰

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.²⁴⁰

May mask certain signs of infection.²⁴⁰

Obtain CBC and chemistry profile periodically during long-term use.²⁴⁰

Specific Populations

Pregnancy

Category C.²⁴⁰ Avoid use in third trimester because of possible premature closure of the ductus arteriosus.²⁴⁰

Lactation

Distributed into milk in humans.²⁴⁰ Discontinue nursing or the drug.²⁴⁰

Pediatric Use

Safety and efficacy not established in children <2 years of age.²⁴⁰

Geriatric Use

Caution advised.²⁴⁰ Geriatric adults appear to tolerate NSAIA-induced adverse effects less well than younger individuals.²⁴⁷ Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.²⁴⁰

Hepatic Impairment

Monitor closely.²⁴⁰

Renal Impairment

Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.²⁴⁰

Common Adverse Effects

Nausea, dyspepsia, GI distress, diarrhea, abdominal pain, flatulence, vomiting, dizziness, headache, asthenia, elevated BP, edema, weight change.²⁴⁰

Interactions for Tolmetin

Protein-bound Drugs

Potential for tolmetin to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.^a Observe for adverse effects.^a

Specific Drugs and Laboratory Tests

Tolmetin Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.^a

Food

Bioavailability reduced 16% when administered immediately after food or with milk. ^{a 240} Peak plasma concentrations reduced 50% when administered immediately after food.^{a 240}

Distribution

Extent

Distributed into human milk.²⁴⁰

Crosses the blood-brain barrier and placenta in animals.^a

Plasma Protein Binding

99%.^a

Elimination

Metabolism

Oxidized in liver to an inactive dicarboxylic acid metabolite.^a

Elimination Route

Excreted in the urine within 24 hours as the dicarboxylic acid metabolite (60%), unchanged tolmetin (20%), and tolmetin conjugates (20%).^a

Half-life

Approximately 1 hour in healthy males.^a

Special Populations

Patients with rheumatoid arthritis: Pharmacokinetic values generally similar to values in healthy individuals; however, increase in renal clearance of tolmetin and its metabolites reported in one study.^a

Stability

Storage

Oral

Capsules and Tablets

Tight, light-resistant containers at 15–30°C.²⁴⁰

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{221 222 223 224 225 226}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^a

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.²⁴⁰

• Risk of serious cardiovascular events (e.g., MI, stroke).^{240 500 508}

• Risk of GI bleeding and ulceration.²⁴⁰

• Risk of serious skin reactions.²⁴⁰ Risk of anaphylactoid and other sensitivity reactions.²⁴⁰

• Risk of hepatotoxicity.²⁴⁰

• Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^{240 500 508}

• Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.²⁴⁰

• Importance of discontinuing tolmetin and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.²⁴⁰ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.²⁴⁰

• Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.²⁴⁰

• Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.⁵⁰⁸

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.²⁴⁰ Importance of avoiding tolmetin in late pregnancy (third trimester).²⁴⁰

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant diseases.²⁴⁰

• Importance of informing patients of other important precautionary information.²⁴⁰ (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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