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.

Carefully consider the potential benefits and risks of TOLECTIN and other treatment options before deciding to use TOLECTIN. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).

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 pediatric patients under 2 years of age (see PRECAUTIONS : Pediatric Use and DOSAGE AND ADMINSTRATION).

Carefully consider the potential benefits and risks of TOLECTIN and other treatment options before deciding to use TOLECTIN. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with TOLECTIN, the dose and frequency should be adjusted to suit an individual patient's needs.

For the relief of rheumatoid arthritis or osteoarthritis, the recommended starting dose for adults 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's response after one or 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.

For the relief of juvenile rheumatoid arthritis, the recommended starting dose for pediatric patients (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).

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

OMP DIVISION, ORTHO-McNEIL PHARMACEUTICAL, INC. Raritan, NJ 08869. Revised February 2006. FDA Rev date: 1/22/2008

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 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 a Whole: Epistaxis

Special Senses: Optic neuropathy, retinal and macular changes

ACE-inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE- inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE- inhibitors.

Aspirin

As with other NSAIDs, concomitant administration of tolmetin sodium and aspirin is not generally recommended because of the potential of increased adverse effects.

Diuretics

Clinical studies, as well as post- marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

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.

Hypoglycemic Agents

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.

Drug/Laboratory Test Interactions

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 Interactions

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%.

Cardiovascular Effects

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDS of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS: Gastrointestinal (GI) Effects-Risk of Ulceration, Bleeding, and Perforation).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including TOLECTIN, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including TOLECTIN, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. TOLECTIN should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal (GI) Effects-Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including TOLECTIN, can cause serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDS occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10- fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and, therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high- risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Acute interstitial nephritis with hematuria, proteinuria, and occasionally nephritic syndrome have been reported in patients treated with TOLECTIN. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which 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 ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical trials regarding the use of TOLECTIN in patients with advanced renal disease. Therefore, treatment with TOLECTIN is not recommended in these patients with advanced renal disease. If TOLECTIN therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients with known prior exposure to TOLECTIN. TOLECTIN should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDS (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including TOLECTIN, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided because it may cause premature closure of the ductus arteriosus (see also PRECAUTIONS: Pregnancy).

General

TOLECTIN cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of TOLECTIN in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Ophthalmological Effects

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

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including TOLECTIN. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes have been reported.

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 a more severe hepatic reaction while on therapy with TOLECTIN. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), TOLECTIN should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including TOLECTIN. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including TOLECTIN, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving TOLECTIN who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, TOLECTIN should no t be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. TOLECTIN, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects).
2. TOLECTIN, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal (GI) Effects-Risk of Ulceration, Bleeding, and Perforation).
3. TOLECTIN, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity, such as itching, and should ask for medical advise when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu- like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, TOLECTIN should be avoided because it will cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, 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.

Pregnancy

Teratogenic Effects: 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, animal reproduction studies are not always predictive of human response. There are no adequate and well- controlled studies in pregnant women. TOLECTIN should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of TOLECTIN on labor and delivery in pregnant women are unknown.

Nursing Mothers

Tolmetin sodium has been shown to be secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tolmetin sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage followed by the administration of activated charcoal.

TOLECTIN is contraindicated in patients with known hypersensitivity to tolmetin sodium.

TOLECTIN should not be given to patients who have experienced asthma, urticaria or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic- like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma ).

TOLECTIN is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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 for 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 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 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 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 osteoarthritis, 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.

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non- Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called "corticosteroids" and "anticoagulants"
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands, and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

This Medication Guide has been approved by the U.S. Food and Drug Administration. August 2007.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

TOLMETIN SODIUM - ORAL

(tole-MET-in SO-dee-um)

WARNING: Nonsteroidal anti-inflammatory drugs (including tolmetin) may rarely increase the risk for a (sometimes fatal) heart attack or stroke. This effect does not apply to low-dose aspirin. (See Drug Interactions section.) The risk may be greater in people with heart disease or increased risk for heart disease (e.g., due to high blood pressure, diabetes), or with longer use. This drug should not be taken right before or after heart bypass surgery (CABG). Also, this drug may infrequently cause serious (rarely fatal) bleeding from the stomach or intestines. This bleeding can occur without warning symptoms at any time during treatment.

Stop taking this medication and seek immediate medical attention if you notice any of the following rare but very serious side effects: chest pain, severe dizziness, trouble breathing, weakness on one side of the body, sudden vision changes, slurred speech, black stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds. (See also Precautions section.)

Talk with your doctor or pharmacist about the risks and benefits of treatment with this medication.

USES: Tolmetin is used alone or with other treatments to reduce pain, swelling, and joint stiffness from rheumatoid arthritis and osteoarthritis. It is also used for juvenile rheumatoid arthritis.

Tolmetin is known as a nonsteroidal anti-inflammatory drug (NSAID).

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using tolmetin and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, usually 3 times a day with a full glass of water (8 ounces or 240 milliliters) or as directed by your doctor. Do not lie down for at least 30 minutes after taking this drug. If stomach upset occurs, take this medication with food, milk, or an antacid (except sodium bicarbonate).

Dosage is based on your medical condition and response to therapy. To reduce your risk of stomach bleeding and other side effects, take this medication at the lowest effective dose for the shortest possible time. Do not increase your dose, take it more frequently, or take it for a longer time than prescribed. Discuss the risks and benefits with your doctor or pharmacist.

Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. It may take 1-2 weeks of taking this drug regularly until you get the full benefit.

Inform your doctor if your condition worsens or if you develop new symptoms.

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, heartburn, dizziness, drowsiness, diarrhea, and headache may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fainting, persistent/severe headache, fast/pounding heartbeat, hearing changes (e.g., ringing in the ears), mental/mood changes, stomach pain, difficult/painful swallowing, swelling of the ankles/feet/hands, sudden/unexplained weight gain.

Stop taking tolmetin and tell your doctor immediately if any of these rare but very serious side effects occur: easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), unexplained stiff neck, change in the amount/color of urine, vision changes.

This drug may rarely cause serious, possibly fatal liver disease. If you notice any of the following rare but very serious side effects, stop taking tolmetin and consult your doctor or pharmacist immediately: persistent nausea/vomiting, severe stomach/abdominal pain, extreme/unusual tiredness, weakness, dark urine, yellowing eyes/skin.

A very serious allergic reaction to this drug is rare. However, stop taking tolmetin and immediately seek medical attention if you notice any of the following symptoms of a serious allergic reaction: rash/blisters, itching, swelling (especially of throat/face), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking tolmetin, tell your doctor or pharmacist if you are allergic to it; or to aspirin or other NSAIDs (e.g., ibuprofen, naproxen, zomepirac, celecoxib); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), recent heart bypass surgery (CABG).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: asthma, bleeding/clotting problems, blood disorders (e.g., anemia), high blood pressure, a severe loss of body water (dehydration), diabetes, heart disease (e.g., congestive heart failure, history of heart attack), kidney disease, liver disease, growths in the nose (nasal polyps), obesity, tobacco use, stomach/intestine/esophagus problems (bleeding sores/ulcer, gastrointestinal bleeding, reflux disease), stroke, swelling of the ankles/feet/hands.

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or taking part in any activity that requires alertness. Avoid alcoholic beverages.

This medicine may cause stomach bleeding. Daily use of alcohol and tobacco, especially when combined with this medicine, may increase your risk for stomach bleeding. Limit alcohol and stop smoking. Consult your doctor or pharmacist for more information.

This medicine contains sodium. If you are on a salt-restricted diet or have any condition that requires you to restrict your intake of salt, consult your doctor or pharmacist about using this drug safely.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, caution is advised when using this drug in the elderly because they may be more sensitive to its side effects, especially stomach bleeding and kidney effects.

This drug is not recommended for use during pregnancy, especially during the last 3 months of pregnancy, due to possible harm to the unborn baby and interference with normal labor/delivery. Discuss the risks and benefits with your doctor.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: cidofovir, ketorolac.

If you are currently using either of the medications listed above, tell your doctor or pharmacist before starting tolmetin.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-platelet drugs (e.g., cilostazol, clopidogrel), bisphosphonates taken by mouth (e.g., alendronate), "blood thinners" (e.g., enoxaparin, heparin, warfarin), corticosteroids (e.g., prednisone), cyclosporine, desmopressin, drugs for high blood pressure (including ACE inhibitors such as captopril, angiotensin II receptor antagonists such as losartan, and beta blockers such as metoprolol), lithium, methotrexate, pemetrexed, probenecid, SSRI antidepressants (e.g., fluoxetine, sertraline), tenofovir, "water pills" (diuretics such as furosemide, hydrochlorothiazide, triamterene).

Check all prescription and nonprescription medicine labels carefully for other pain/fever drugs (NSAIDs such as aspirin, celecoxib, ibuprofen). These drugs are similar to this medication, so taking one of these drugs while also taking this medication may increase your risk of side effects. However, if your doctor has prescribed low doses of aspirin to prevent heart attack or stroke (usually at dosages of 81-325 milligrams a day), you should continue to take the aspirin. Daily use of NSAIDs (e.g., ibuprofen) may decrease aspirin's ability to prevent heart attack/stroke. Consult your doctor or pharmacist for more details and to discuss other possible treatments (e.g., acetaminophen) for your pain/fever.

This product can affect the results of certain lab tests (e.g., protein in urine), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center. Symptoms of overdose may include: severe stomach pain, vomit that looks like coffee grounds, extreme drowsiness, slow/shallow breathing, seizures.

NOTES: Do not share this drug with others.

Laboratory and/or medical tests (e.g., blood pressure, complete blood count, eye exams, liver and kidney function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.