Tolmetin Sodium

TOLECTIN DS (tolmetin sodium) capsules for oral administration contain tolmetin sodium as the dihydrate in an amount equivalent to 400 mg of tolmetin. Each capsule contains 36 mg (1.568 mEq) of sodium and the following inactive ingredients: gelatin, magnesium stearate, corn starch, talc, FD&C Red No. 3, FD&C Yellow No. 6 and titanium dioxide.

TOLECTIN 600 (tolmetin sodium) tablets for oral administration contain tolmetin sodium as the dihydrate in an amount equivalent to 600 mg of tolmetin. Each tablet contains 54 mg (2.35 mEq) of sodium and the following inactive ingredients: cellulose, silicon dioxide, crospovidone, hydroxypropyl methyl cellulose, magnesium stearate, polyethylene glycol, corn starch, titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10.

The pKa of tolmetin is 3.5 and tolmetin sodium is freely soluble in water.

Tolmetin sodium is a nonselective nonsteroidal anti- inflammatory agent. The structural formula is:

Sodium 1- methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate.

Studies in animals have shown TOLECTIN (tolmetin sodium) to possess anti- inflammatory, analgesic, and antipyretic activity. In the rat, TOLECTIN (tolmetin sodium) prevents the development of experimentally induced polyarthritis and also decreases established inflammation.

The mode of action for TOLECTIN (tolmetin sodium) is not known. However, studies in laboratory animals and man have demonstrated that the anti- inflammatory action of TOLECTIN (tolmetin sodium) is not due to pituitary-adrenal stimulation. TOLECTIN (tolmetin sodium) inhibits prostaglandin synthetasein vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti- inflammatory action. TOLECTIN (tolmetin sodium) does not appear to alter the course of the underlying disease in man.

In patients with rheumatoid arthritis and in normal volunteers, tolmetin sodium is rapidly and almost completely absorbed with peak plasma levels being reached within 30-60 minutes after an oral therapeutic dose. In controlled studies, the time to reach peak tolmetin plasma concentration is approximately 20 minutes longer following administration of a 600 mg tablet, compared to an equivalent dose given as 200 mg tablets. The clinical meaningfulness of this finding, if any, is unknown. Tolmetin displays a biphasic elimination from the plasma consisting of a rapid phase with a half- life of 1 to 2 hours followed by a slower phase with a half- life of about 5 hours. Peak plasma levels of approximately 40 mg/mL are obtained with a 400 mg oral dose. Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. An 18-day multiple dose study demonstrated no accumulation of tolmetin when compared with a single dose.

In two fecal blood loss studies of 4 to 6 days duration involving 15 subjects each, TOLECTIN (tolmetin sodium) did not induce an increase in blood loss over that observed during a 4-day drug- free control period. In the same studies, aspirin produced a greater blood loss than occurred during the drug-free control period, and a greater blood loss than occurred during the TOLECTIN (tolmetin sodium) treatment period. In one of the two studies, indomethacin produced a greater fecal blood loss than occurred during the drug- free control period; in the second study, indomethacin did not induce a significant increase in blood loss.

TOLECTIN (tolmetin sodium) is effective in treating both the acute flares and in the long-term management of the symptoms of rheumatoid arthritis, osteoarthritis and juvenile rheumatoid arthritis.

In patients with either rheumatoid arthritis or osteoarthritis, TOLECTIN (tolmetin sodium) is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients.

In patients with juvenile rheumatoid arthritis, TOLECTIN (tolmetin sodium) is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. Mean SGOT values, initially elevated in patients on previous aspirin therapy, remained elevated in the aspirin group and decreased in the TOLECTIN (tolmetin sodium) group.

TOLECTIN (tolmetin sodium) has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. TOLECTIN (tolmetin sodium) should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased.

Prototypical NSAIA; pyrrole acetic acid derivative. a

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

Contraindications

• 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

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 information500 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.)

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 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.)

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

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

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

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

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

Tinnitus reported; deterioration in hearing reported rarely.a

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

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

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

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

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

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

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

Monitor closely.240

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

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

• 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.)

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