Tolmetin
Class: Other Nonsteroidal Anti-inflammatory Agents
VA Class: MS120
Chemical Name: Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate
CAS Number: 64490-92-2
Medically reviewed by Drugs.com. Last updated on Nov 9, 2020.
Warning
Special Alerts:
[Posted 10/15/2020]
AUDIENCE: Consumer, Patient, Health Professional, Pharmacy
ISSUE: FDA is warning that use of NSAIDs around 20 weeks or later in pregnancy may cause rare but serious kidney problems in an unborn baby. This can lead to low levels of amniotic fluid surrounding the baby and possible complications.
For prescription NSAIDs, FDA is requiring changes to the prescribing information to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.
For over-the-counter (OTC) NSAIDs intended for use in adults, FDA will also update the Drug Facts labels, available at: [Web]. These labels already warn to avoid using NSAIDs during the last 3 months of pregnancy because the medicines may cause problems in the unborn child or complications during delivery. The Drug Facts labels already advise pregnant and breastfeeding women to ask a health care professional before using these medicines.
BACKGROUND:
NSAIDs
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are a class of medicines available by prescription and OTC. They are some of the most commonly used medicines for pain and fever.
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are used to treat medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu.
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work by blocking the production of certain chemicals in the body that cause inflammation.
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are available alone and combined with other medicines. Examples of NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, and celecoxib.
Common side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.
RECOMMENDATION:
Consumers/Patients
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If you are pregnant, do not use NSAIDs at 20 weeks or later in pregnancy unless specifically advised to do so by your health care professional because these medicines may cause problems in your unborn baby.
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Many OTC medicines contain NSAIDs, including those used for pain, colds, flu, and insomnia, so it is important to read the Drug Facts labels, available at: [Web], to find out if the medicines contain NSAIDs.
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Talk to your health care professional or pharmacist if you have questions or concerns about NSAIDs or which medicines contain them.
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Other medicines, such as acetaminophen, are available to treat pain and fever during pregnancy. Talk to your pharmacist or health care professional for help deciding which might be best.
Health Care Professionals
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FDA recommends that health care professionals should limit prescribing NSAIDs between 20 to 30 weeks of pregnancy and avoid prescribing them after 30 weeks of pregnancy. If NSAID treatment is determined necessary, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found. FDA is warning that use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
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These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
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Oligohydramnios is often, but not always, reversible with treatment discontinuation.
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Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
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If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. As currently described in the NSAID labels, avoid prescribing NSAIDs at 30 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus.
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The above recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy.
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Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice.
For more information visit the FDA website at: [Web] and [Web].
Warning
- Cardiovascular Risk
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Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).240 500 502 508 Risk may occur early in treatment and may increase with duration of use.500 502 505 506 508 (See Cardiovascular Thrombotic Effects under Cautions.)
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Contraindicated in the setting of CABG surgery.508
- GI Risk
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Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).240 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.240 Geriatric individuals are at greater risk for serious GI events.240 (See GI Effects under Cautions.)
Introduction
Prototypical NSAIA; pyrrole acetic acid derivative. a
Uses for Tolmetin
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Consider potential benefits and risks of tolmetin therapy as well as alternative therapies before initiating therapy with the drug.240 Use lowest possible effective dosage and shortest duration of therapy consistent with patient's treatment goals.240
Inflammatory Diseases
Symptomatic treatment of osteoarthritis and rheumatoid arthritis.240
Management of juvenile rheumatoid arthritis in children ≥2 years of age.240
Has been reported to be effective in the management of ankylosing spondylitis† (late stages did not respond as well as early stages); has also been used with some success in the treatment of adhesive capsulitis shoulder† (frozen shoulder), radiohumeral bursitis† (tennis elbow), and local trauma† (e.g., recent sprains).a
Tolmetin Dosage and Administration
General
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Consider potential benefits and risks of tolmetin therapy as well as alternative therapies before initiating therapy with the drug.240
Administration
Oral Administration
Administer orally 3 or 4 times daily.240
Administration with antacids (i.e., antacid containing aluminum and magnesium hydroxides) may minimize adverse GI effects.240
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Available as tolmetin sodium; dosage expressed in terms of tolmetin.240
To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.240 Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.240
Pediatric Patients
Inflammatory Diseases
Juvenile Rheumatoid Arthritis
OralChildren ≥2 years of age: Initially, 20 mg/kg daily in 3 or 4 divided doses.240 Adjust dosage based on response and tolerance.240
Usual effective dosage: 15–30 mg/kg daily.240
Adults
Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
OralInitially, 400 mg 3 times daily, preferably including a dose on arising and at bedtime.240 Adjust dosage based on response (after 1 or 2 weeks) and tolerance.a
Usual effective dosage: 600 mg to 1.8 g daily in 3 divided doses.240
Ankylosing Spondylitis†
Oral600 mg to 1.6 g daily in divided dose has been used.a
Adhesive Capsulitis Shoulder† (frozen shoulder), Radiohumeral Bursitis† (tennis elbow), Local Trauma† (e.g., recent sprains)
Oral>600 mg or 1.2 g daily in divided doses has been used.a
Prescribing Limits
Pediatric Patients
Inflammatory Diseases
Juvenile Rheumatoid Arthritis
OralDosages >30 mg/kg daily have not been studied and are not recommended.240
Adults
Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
OralDosages >1.8 g daily have not been studied and are not recommended.240
Special Populations
Renal Impairment
Reduce dosage if necessary.240
Geriatric Patients
Select dosage with caution (potential for age-related renal function decline).247
Cautions for Tolmetin
Contraindications
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
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Known hypersensitivity to tolmetin or any ingredient in the formulation.240
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History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.240
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In the setting of CABG surgery.508
Warnings/Precautions
Warnings
Cardiovascular Thrombotic Effects
NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500 502 508
Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published 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.)
GI Effects
Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.200 201 212 240 227 230 237
For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;203 227 228 229 alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)203 227 228 or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).228
Hypertension
Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.240 Use with caution in patients with hypertension; monitor BP.240
Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.240 508 509 (See Specific Drugs and Laboratory Tests under Interactions.)
Heart Failure and Edema
Fluid retention and edema reported.240 508
NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.500 501 504 507 508
NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.508 (See Specific Drugs and Laboratory Tests under Interactions.)
Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.508
Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507
Renal Effects
Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.240
Potential for overt renal decompensation.204 240 Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.204 240 243 247 (See Renal Impairment under Cautions.)
Sensitivity Reactions
Hypersensitivity Reactions
Anaphylactoid reactions reported. 240
Immediate medical intervention and discontinuance for anaphylaxis.240
Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.240
Dermatologic Reactions
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.240 Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).240
General Precautions
Ocular and Otic Effects
Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.240
Tinnitus reported; deterioration in hearing reported rarely.a
Hepatic Effects
Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs. 240
Elevations of serum ALT or AST reported.240 Elevations of serum alkaline phosphatase also reported.a
Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.240 Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.240
Hematologic Effects
Anemia reported rarely.240 Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.240
Small and transient decreases in hemoglobin concentration or hematocrit (not associated with GI bleeding), leukopenia (including granulocytopenia), thrombocytopenia, and hemolytic anemia reported.a One case of fatal agranulocytosis reported. a
May inhibit platelet aggregation and prolong bleeding time.240
Other Precautions
Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.240
May mask certain signs of infection.240
Obtain CBC and chemistry profile periodically during long-term use.240
Specific Populations
Pregnancy
Category C.240 Avoid use in third trimester because of possible premature closure of the ductus arteriosus.240
Lactation
Distributed into milk in humans.240 Discontinue nursing or the drug.240
Pediatric Use
Safety and efficacy not established in children <2 years of age.240
Geriatric Use
Caution advised.240 Geriatric adults appear to tolerate NSAIA-induced adverse effects less well than younger individuals.247 Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.240
Hepatic Impairment
Monitor closely.240
Renal Impairment
Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.240
Common Adverse Effects
Nausea, dyspepsia, GI distress, diarrhea, abdominal pain, flatulence, vomiting, dizziness, headache, asthenia, elevated BP, edema, weight change.240
Interactions for Tolmetin
Protein-bound Drugs
Potential for tolmetin to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.a Observe for adverse effects.a
Specific Drugs and Laboratory Tests
Drug or Test |
Interaction |
Comments |
---|---|---|
ACE inhibitors |
Reduced BP response to the ACE inhibitor240 |
Monitor BP240 |
Angiotensin II receptor antagonists |
Reduced BP response to angiotensin II receptor antagonist247 |
Monitor BP247 |
Anticoagulants (warfarin) |
Possible bleeding complications240 Increased PT and bleeding reported rarelya |
Caution advised 240 |
Antidiabetic agents |
Administration with insulin or sulfonylureas does not appear to alter the clinical effects of the NSAIA or the antidiabetic agenta 240 |
|
Diuretics (furosemide, thiazides) |
Reduced natriuretic effects 240 |
Monitor for diuretic efficacy and renal failure240 |
Lithium |
Increase plasma lithium concentrations240 |
Monitor for lithium toxicity240 |
Methotrexate |
Possible increased and prolonged blood concentrations of methotrexate205 206 207 208 209 210 211 |
Use with caution240 |
NSAIAs |
NSAIAs including aspirin: Increased risk of GI ulceration or other complications 240 Aspirin: No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs240 502 508 |
Concomitant use not recommended240 |
Tests for urinary protein |
False-positive results with tests that use sulfosalicylic acid reagent240 |
Use dye-impregnated reagent strips (e.g., Albustix, Uristix)240 |
Tolmetin Pharmacokinetics
Absorption
Bioavailability
Well absorbed following oral administration.a
Food
Bioavailability reduced 16% when administered immediately after food or with milk. a 240 Peak plasma concentrations reduced 50% when administered immediately after food.a 240
Distribution
Extent
Distributed into human milk.240
Crosses the blood-brain barrier and placenta in animals.a
Plasma Protein Binding
99%.a
Elimination
Metabolism
Oxidized in liver to an inactive dicarboxylic acid metabolite.a
Elimination Route
Excreted in the urine within 24 hours as the dicarboxylic acid metabolite (60%), unchanged tolmetin (20%), and tolmetin conjugates (20%).a
Half-life
Approximately 1 hour in healthy males.a
Special Populations
Patients with rheumatoid arthritis: Pharmacokinetic values generally similar to values in healthy individuals; however, increase in renal clearance of tolmetin and its metabolites reported in one study.a
Stability
Storage
Oral
Capsules and Tablets
Tight, light-resistant containers at 15–30°C.240
Actions
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Inhibits cyclooxygenase-1 (COX-1) and COX-2.221 222 223 224 225 226
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Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.a
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
-
Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.240
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Risk of serious cardiovascular events (e.g., MI, stroke).240 500 508
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Risk of GI bleeding and ulceration.240
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Risk of serious skin reactions.240 Risk of anaphylactoid and other sensitivity reactions.240
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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
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Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.240
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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
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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
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Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.508
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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
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Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant diseases.240
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Importance of informing patients of other important precautionary information.240 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
400 mg (of tolmetin)* |
Tolmetin Sodium Capsules |
|
Tablets |
200 mg (of tolmetin)* |
Tolmetin Sodium Tablets |
||
Tablets, film-coated |
600 mg (of tolmetin)* |
Tolmetin Sodium Tablets |
AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 9, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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