TOLECTIN 200 (tolmetin sodium) tablets for oral administration contain tolmetin sodium as the dihydrate in an amount equivalent to 200 mg of tolmetin (scored for 100 mg). Each tablet contains 18 mg (0.784 mEq) of sodium and the following inactive ingredients: cellulose, magnesium stearate, silicon dioxide, corn starch and talc.

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 nonsteroidal anti-inflammatory agent.

The structural formula is:

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

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

The mode of action of TOLECTIN is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of TOLECTIN is not due to pituitary-adrenal stimulation. TOLECTIN inhibits prostaglandin synthetase in 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 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 one to 2 hours followed by a slower phase with a half-life of about 5 hours. Peak plasma levels of approximately 40 µg/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 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 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 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 osteaoarthritis, TOLECTIN 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 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 group.

TOLECTIN has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. TOLECTIN 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.

TOLECTIN (tolmetin sodium) is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. TOLECTIN is indicated in the treatment of acute flares and the long-term management of the chronic disease.

TOLECTIN is also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of TOLECTIN have not been established in children under 2 years of age (see PRECAUTIONS -- Pediatric Use and DOSAGE AND ADMINISTRATION ).

CONTRAINDICATIONS

Anaphylactoid reactions have been reported with TOLECTIN as with other nonsteroidal anti-inflammatory drugs. Because of the possibility of cross-sensitivity to other nonsteroidal anti-inflammatory drugs, particularly zomepirac sodium, anaphylactoid reactions may be more likely to occur in patients who have exhibited allergic reactions to these compounds. For this reason, TOLECTIN should not be given to patients in whom aspirin and other nonsteroidal anti-inflammatory drugs induce symptoms of asthma, rhinitis, urticaria and other symptoms of allergic or anaphylactoid reactions. Patients experiencing anaphylactoid reactions on TOLECTIN should be treated with conventional therapy, such as epinephrine, antihistamines and/or steroids.

Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy:

Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time, with or without symptoms, in patients treated chronically with NSAID (Nonsteroidal Anti-Inflammatory Drug) therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developng early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAID' even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.

Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAID' in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.

PRECAUTIONS

General

Because of ocular changes observed in animals and reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is recommended that patients who develop visual disturbances during treatment with TOLECTIN have ophthalmologic evaluations.

As with other nonsteroidal anti-inflammatory drugs, 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 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 a 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 an 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 heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.

Since TOLECTIN and its metabolites are eliminated primarily by the kidneys, patients with impaired renal function should be closely monitored, and it should be anticipated that they will require lower doses.

TOLECTIN prolongs bleeding time. Patients who may be adversely affected by prolongation of bleeding time should be carefully observed when TOLECTIN is administered.

In patients receiving concomitant TOLECTIN-steroid therapy, any reduction in steroid dosage should be gradual to avoid the possible complications of sudden steroid withdrawal.

Peripheral edema has been reported in some patients receiving TOLECTIN therapy. Therefore, as with other nonsteroidal anti-inflammatory drugs, TOLECTIN should be used with caution in patients with compromised cardiac function, hypertension, or other conditions predisposing to fluid retention.

The antipyretic and anti-inflammatory activities of the drug may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting complications of presumed non-infectious, non-inflammatory painful conditions.

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 TOLECTIN. Severe hepatic reactions, including jaundice and fatal hepatitis, have been reported with TOLECTIN as with other nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), TOLECTIN should be discontinued.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tolmetin sodium did not possess any carcinogenic liability in the following long-term studies: a 24-month study in rats at doses as high as 75 mg/kg/day, and an 18-month study in mice at doses as high as 50 mg/kg/day.

No mutagenic potential of tolmetin sodium was found in the Ames Salmonella-Microsomal Activation Test.

Reproductive studies revealed no impairment of fertility in animals. Effects on parturition have been shown, however, as with other prostaglandin inhibitors. This information is detailed in the Pregnancy section below.

Pregnancy

Pregnancy Category C. Reproduction studies in rats and rabbits at doses up to 50 mg/kg (1.5 times the maximum clinical dose based on a body weight of 60 kg) revealed no evidence of teratogenesis or impaired fertility due to TOLECTIN. However, TOLECTIN is an inhibitor of prostaglandin synthetase. Drugs in this class have known effects on the fetal cardiovascular system which may cause constriction of the ductus arteriosus in utero during the third trimester of pregnancy, which may result in persistent pulmonary hypertension of the newborn.

There are no adequate and well-controlled studies in pregnant women. TOLECTIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-Teratogenic Effects

Prostaglandin inhibitors have also been shown to increase the incidence of dystocia and delayed parturition in animals.

Nursing Mothers

TOLECTIN has been shown to be secreted in human milk. Because of the possible adverse effects of prostaglandin inhibiting drugs on neonates, use in nursing mothers should be avoided.

Pediatric Use

The safety and effectiveness of TOLECTIN in children under 2 years of age have not been established.

Drug Interactions

The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants.

In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents.

Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate.

Laboratory Tests

Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see -- Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy ).

Drug/Laboratory Test Interaction

The metabolites of tolmetin sodium in urine have been found to give positive tests for proteinuria using tests which rely on acid precipitation as their endpoint (e.g. sulfosalicylic acid). No interference is seen in the tests for proteinuria using dye-impregnated commercially available reagent strips (e.g., Albustix®, Uristix®, etc.).

Drug-Food Interaction

In a controlled single dose study, administration of TOLECTIN with milk had no effect on peak plasma tolmetin concentrations, but decreased total tolmetin bioavailability by 16%. When TOLECTIN was taken immediately after a meal, peak plasma tolmetin concentrations were reduced by 50% while total bioavailability was again decreased by 16%.

Information for Patients

TOLECTIN, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.

NSAID' (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in the management of arthritis, but they also may be commonly employed for conditions which are less serious.

Physicians may wish to discuss with their patients the potential risks (see , PRECAUTIONS , and ADVERSE REACTIONS sections) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAID's may represent an acceptable alternative to both the patient and physician.

ADVERSE REACTIONS

The adverse reactions which have been observed in clinical trials encompass observations in about 4370 patients treated with TOLECTIN (tolmetin sodium), over 800 of whom have undergone at least one year of therapy. These adverse reactions, reported below by body system, are among those typical of nonsteroidal anti-inflammatory drugs and, as expected, gastrointestinal complaints were most frequent. In clinical trials with TOLECTIN, about 10% of patients dropped out because of adverse reactions, mostly gastrointestinal in nature.

Incidence Greater Than 1%

The following adverse reactions which occurred more frequently than 1 in 100 were reported in controlled clinical trials.

Gastrointestinal:   Nausea (11%), dyspepsia,* gastrointestinal distress,* abdominal pain,* diarrhea,* flatulence,* vomiting,* constipation, gastritis, and peptic ulcer. Forty percent of the ulcer patients had a prior history of peptic ulcer disease and/or were receiving concomitant anti-inflammatory drugs including corticosteroids, which are known to produce peptic ulceration.

Body as a Whole:   Headache,* asthenia,* chest pain

Cardiovascular:   Elevated blood pressure,* edema*

Central Nervous System: Dizziness,* drowsiness, depression

Metabolic/Nutritional:   Weight gain,* weight loss*

Dermatologic:   Skin irritation

Special Senses:   Tinnitus, visual disturbance

Hematologic:   Small and transient decreases in hemoglobin and hematocrit not associated with gastrointestinal bleeding have occurred. These are similar to changes reported with other nonsteroidal anti-inflammatory drugs.

Urogenital:   Elevated BUN, urinary tract infection

*Reactions occurring in 3% to 9% of patients treated with TOLECTIN. Reactions occurring in fewer than 3% of the patients are unmarked.

Incidence Less Than 1%

(Causal Relationship Probable)

The following adverse reactions were reported less frequently than 1 in 100 in controlled clinical trials or were reported since marketing. The probability exists that there is a causal relationship between TOLECTIN and these adverse reactions.

Gastrointestinal:   Gastrointestinal bleeding with or without evidence of peptic ulcer, perforation, glossitis, stomatitis, hepatitis, liver function abnormalities

Body as a Whole:   Anaphylactoid reactions, fever, lymphadenopathy, serum sickness

Hematologic:   Hemolytic anemia, thrombocytopenia, granulocytopenia, agranulocytosis

Cardiovascular:   Congestive heart failure in patients with marginal cardiac function

Dermatologic:   Urticaria, purpura, erythema multiforme, toxic epidermal necrolysis

Urogenital:   Hematuria, proteinuria, dysuria, renal failure

Incidence Less Than 1%

(Causal Relationship Unknown)

Other adverse reactions were reported less frequently than 1 in 100 in controlled clinical trials or were reported since marketing, but a causal relationship between TOLECTIN and the reaction could not be determined. These rarely reported reactions are being listed as alerting information for the physician since the possibility of a causal relationship cannot be excluded.

Body as Whole:   Epistaxis

Special Senses:   Optic neuropathy, retinal and macular changes

MANAGEMENT OF OVERDOSAGE

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

In adults with rheumatoid arthritis or osteoarthritis, the recommended starting dose is 400 mg three times daily (1200 mg daily), preferably including a dose on arising and a dose at bedtime. To achieve optimal therapeutic effect the dose should be adjusted according to the patient' response after one to two weeks. Control is usually achieved at doses of 600-1800 mg daily in divided doses (generally t.i.d.). Doses larger than 1800 mg/day have not been studied and are not recommended.

The recommended starting dose for children (2 years and older) 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.

A therapeutic response to TOLECTIN (tolmetin sodium) can be expected in a few days to a week. Progressive improvement can be anticipated during succeeding weeks of therapy. If gastrointestinal symptoms occur, TOLECTIN can be administered with antacids other than sodium bicarbonate. TOLECTIN bioavailability and pharmacokinetics are not significantly affected by acute or chronic administration of magnesium and aluminum hydroxides; however, bioavailability is affected by food or milk (see PRECAUTIONS -- Drug-Food Interaction ).

HOW SUPPLIED

TOLECTIN® 200 (tolmetin sodium) tablets 200 mg (white, scored, imprinted "TOLECTIN," "200" and "McNEIL"), NDC 0045-0412, bottles of 100.

TOLECTIN® DS (tolmetin sodium) capsules 400 mg (colored orange opaque, with contrasting parallel bands, imprinted "TOLECTIN DS" and "McNEIL"), NDC 0045-0414, bottles of 100, 500.

TOLECTIN® 600 (tolmetin sodium) tablets 600 mg (colored orange, film coated, imprinted "TOLECTIN 600" and "McNEIL"), NDC 0045-0416, bottles of 100 and 500.

Dispense in tight, light-resistant container as defined in the official compendium.

Store at controlled room temperature (15°-30°C, 59°-86°F). Protect from light.

McNeil Pharmaceutical, McNEILAB, Inc.

Spring House, PA 19477

Revised June 1997                                    643-10-089-2

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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