TOLECTIN® Janssen-Ortho Tolmetin Sodium Anti-inflammatory–Analgesic–Antipyretic
Action and Clinical
Tolmetin has demonstrated anti-inflammatory, analgesic and antipyretic properties in classical animal test systems. In patients with rheumatoid arthritis, the anti-inflammatory action has been shown by a reduction in joint swelling, pain and duration of morning stiffness, as well as by enhanced grip strength, increased mobility and increased delay in the onset of fatigue.
Studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation.
Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This inhibition of prostaglandin synthesis may be responsible for the anti-inflammatory action of the drug.
Clinical trials in human subjects have shown that the administration of tolmetin, in daily doses of 1 200 mg, is similar in alleviating arthritis symptomatology to ASA, in daily doses of 3 900 mg. It has been shown that gastrointestinal bleeding is less severe with tolmetin than with ASA.
Pharmacokinetics: In man, tolmetin is rapidly and completely absorbed with attainment of peak plasma levels within 20 to 60 minutes following an oral dose. The drug is eliminated from the plasma with a mean half-life of 1 to 3 hours. Peak plasma levels of about 40 g/mL are obtained with an oral dose of 400 mg. 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-free acid.
Tolmetin is extensively (>99%) bound to plasma albumin (see Precautions, Drug Interactions).
Indications And Clinical Uses:
The treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.
Peptic ulcer or active inflammatory disease of the gastrointestinal system. Known or suspected hypersensitivity to the drug. Tolmetin should not be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals.
Warnings in Clinical States:
Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal, have been reported during therapy with NSAIDs including tolmetin.
Tolmetin should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.
Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.
Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions).
Pregnancy: Safe conditions for the use of tolmetin in pregnancy have not been determined and, therefore, such use is not recommended. Rats treated with 10 to 50 mg/kg/day during the last part of pregnancy demonstrated prolonged parturition which increased hemorrhage and increased pup mortality.
Lactation: Tolmetin has been shown to be secreted in human milk. Therefore, because of the possible adverse effects of prostaglandin inhibiting drugs on neonates, use in nursing mothers should be avoided.
Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, tolmetin should be discontinued, an appropriate treatment instituted and the patient closely monitored.
There is no definitive evidence that the concomitant administration of histamine H 2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of tolmetin therapy when and if these adverse reactions appear.
Hypersensitivity Reactions: Anaphylactoid reactions have been reported with tolmetin. Because of the possibility of cross-sensitivity to other NSAIDs, particularly zomepirac, anaphylactoid reactions may be more likely to occur in patients who have exhibited allergic reactions to these compounds (see Contraindications).
Renal Function: As with other NSAIDs, long-term administration of tolmetin to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of renal failure, acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.
Tolmetin and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function. In these cases lower doses of tolmetin should be anticipated and patients carefully monitored.
The metabolites of tolmetin in urine have been found to give false positive tests for proteinuria using any test which relies on acid precipitation as its endpoint (e.g. sulfosalicylic acid). No interference is seen in the test for proteinuria using Albustix Reagent Strips.
During long-term therapy kidney function should be monitored periodically.
Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. 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 more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this drug as with other NSAIDs. Although such reactions are rare, if abnormal liver tests persist, or worse, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.
During long-term therapy, liver function tests should be monitored periodically. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.
Fluid and Electrolyte Balance: Fluid retention and edema have been reported in about 7% of patients treated with tolmetin. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Tolmetin should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.
Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.
Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when tolmetin is administered.
Blood dyscrasias associated with the use of NSAIDs are rare, but can have severe consequences.
Infection: In common with other anti-inflammatory drugs, tolmetin may mask the usual signs of infection.
Ophthalmology: Blurred and/or diminished vision has been reported with the use of tolmetin and other NSAIDs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.
Geriatrics: As with other anti-inflammatory drugs, tolmetin should be used with caution in elderly patients, and the dosage should be adjusted individually. No data on pharmacokinetic studies involving elderly patients are available.
Children: The safety and effectiveness of tolmetin have not been established in infants under 2 years of age.
Tolmetin is highly bound to plasma proteins. This may lead to interaction with anticoagulants, sulfonylurea hypoglycemic agents, sulfonamides, phenytoin, lithium and certain chemotherapeutic agents such as methotrexate.
Concomitant administration of ASA results in decreased peak serum concentrations of tolmetin and slight increases in both clearance and apparent half-life. The clinical significance of these changes is unknown.
In clinical use, cases of increased prothrombin time and bleeding have been reported in patients taking anticoagulants. Therefore, such patients should be carefully monitored when tolmetin is administered. The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin did not alter the prothrombin time of normal volunteers.
In a study in adult diabetic patients under treatment with either sulfonylureas or insulin there was no change in the clinical effects of either tolmetin or the hypoglycemic agents. However, if there are side effects such as nausea, anorexia or vomiting, the dose of the antidiabetic used may have to be reduced to prevent hypoglycemic reaction.
Tolmetin causes water retention and therefore may interfere with diuretics in the treatment of hypertension.
In patients receiving concomitant steroid therapy, any reduction in steroid dosage should be gradual to avoid the possible complications of sudden steroid withdrawal.
Drug-Food Interaction: 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%.
The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.
The following adverse reactions were reported in controlled clinical trials and/or since the drug has been marketed.
Gastrointestinal: nausea (11%), dyspepsia, gastrointestinal distress, abdominal pain, diarrhea, flatulence, vomiting, constipation, gastritis, peptic ulcer, gastrointestinal bleeding with or without evidence of peptic ulcer, glossitis, stomatitis, hepatitis.
Borderline elevations of liver function tests may occur in up to 15% of patients; less than 1% of patients had clinically significant elevations.
Hypersensitivity: anaphylactoid reactions, fever, lymphadenopathy, serum sickness.
Cardiovascular: elevated blood pressure, edema, congestive heart failure in patients with marginal cardiac function, palpitations.
CNS: headache, dizziness, drowsiness, depression, aseptic meningitis (causal relationship unknown).
Metabolic/Nutritional: asthenia, weight gain, weight loss.
Dermatologic: skin irritation, urticaria, purpura, erythema multiforme, toxic epidermal necrolysis.
Special Senses: tinnitus, visual disturbance, optic neuropathy, retinal and macular changes.
Hematologic: small and transient decreases in hemoglobin and hematocrit not associated with gastrointestinal bleeding, hemolytic anemia, thrombocytopenia, granulocytopenia, agranulocytosis, leukopenia.
Renal: elevated BUN, urinary tract infection, hematuria, proteinuria, dysuria, interstitial nephritis, hyperuricemia, renal failure.
Miscellaneous: chest pain, epistaxis (causal relationship unknown).
*Reactions occurring in 3 to 9% of patients treated with tolmetin. Reactions occurring in fewer than 3% of the patients are unmarked.
Symptoms And Treatment Of Overdose:
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, followed by the administration of activated charcoal.
Dosage And Administration:
Adults: Rheumatoid Arthritis and Ankylosing Spondylitis: The recommended starting dose of tolmetin is 1 200 mg/day, in 3 doses. The dose should be individualized to achieve the minimum effective maintenance dose which lies between 600 and 1 800 mg/day given t.i.d. or q.i.d. Doses larger than 2 000 mg/day have not been studied and are not recommended. A 600 mg tablet is available for patients who require 1 800 mg/day in 3 divided doses.
Osteoarthritis: The recommended starting dose of tolmetin is 800 to 1 200 mg/day given t.i.d. or q.i.d. The dose should be adjusted either upwards or downwards to achieve the minimum effective maintenance dose. The maintenance dose usually lies between 600 and 1 600 mg/day given t.i.d. or q.i.d. Doses larger than 1 600 mg*/day have not been studied and are not recommended.
Expressed as tolmetin-free acid.
Children (2 years and older): The recommended starting dose in juvenile rheumatoid arthritis is 20 mg/kg/day in divided doses (t.i.d. or q.i.d.). When control has been achieved the usual dose ranges from 15 to 30 mg/kg/day. Doses higher than 30 mg/kg/day have not been studied and, therefore, are not recommended.
Abdominal discomfort which may occur with tolmetin can be minimized by the administration of the drug with meals, milk (see Precautions, Drug-Food Interaction) or antacids other than sodium bicarbonate.
Tolmetin should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse effects is increased.
Tolmetin may also be added to the treatment regimen of patients receiving gold or corticosteroids.
Availability And Storage:
Tolectin 200: Each round, hard, flat-faced, beveled, scored, cream-colored tablet, engraved “TOLECTIN” and “200” on one side and engraved “McNEIL” on the other, contains: tolmetin sodium dihydrate equivalent to 200 mg of tolmetin (free acid). Nonmedicinal ingredients: cellulose, colloidal silicon dioxide, cornstarch, magnesium stearate and talc. Energy: 0.560 kJ (0.133 kcal). Sodium: <1 mmol (18 mg). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 100.
Tolectin 400: Each hard, orange-opaque, gelatin capsule containing a granular cream colored powder with a ring of grey-blue color located around the cap and body of the capsule, spin-printed grey-blue “McNEIL” and “TOLECTIN-DS” around each halves of the capsule, contains: tolmetin sodium dihydrate equivalent to 400 mg of tolmetin (free acid). Nonmedicinal ingredients: cornstarch, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, magnesium stearate, talc and titanium dioxide. Energy: 1.405 kJ (0.334 kcal). Sodium: 1.568 mmol (36 mg). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 100.
Tolectin 600: Each orange, film-coated oval, biconvex tablet, printed “McNEIL”, “TOLECTIN” and “600” on one side, contains: tolmetin sodium dihydrate equivalent to 600 mg of tolmetin (free acid). Nonmedicinal ingredients: cellulose, colloidal silicon dioxide, crospovidone, D&C Yellow No. 10, hydroxypropyl methylcellulose and polyethylene glycol. Energy: 3.017 kJ (0.721 kcal). Sodium: 2.35 mmol (54 mg). Gluten-, lactose-, sodium metabisulfite- and tartrazine-free. Bottles of 100.
Tolectin tablets, capsules and caplets should be stored at controlled room temperature (15 to 30°C) in well-closed containers. Tolectin 600 caplets should be protected from light.
TOLECTIN® Janssen-Ortho Tolmetin Sodium Anti-inflammatory–Analgesic–Antipyretic