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Meclofenamate

Class: Other Nonsteroidal Anti-inflammatory Agents
VA Class: MS120
CAS Number: 6385-02-0

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

  • are a class of medicines available by prescription and OTC. They are some of the most commonly used medicines for pain and fever.

  • are used to treat medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu.

  • work by blocking the production of certain chemicals in the body that cause inflammation.

  • 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

  • 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.

  • 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.

  • Talk to your health care professional or pharmacist if you have questions or concerns about NSAIDs or which medicines contain them.

  • 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

  • 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.

  • 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.

  • Oligohydramnios is often, but not always, reversible with treatment discontinuation.

  • 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.

  • 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.

  • The above recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy.

  • 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

  • Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).146 147 500 502 508 Risk may occur early in treatment and may increase with duration of use.500 502 505 506 508 (See Cardiovascular Thrombotic Effects under Cautions.)

  • Contraindicated in the setting of CABG surgery.508

    GI Risk

  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).100 108 109 117 145 146 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.100 108 109 117 146 Geriatric individuals are at greater risk for serious GI events.100 146 (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA;100 a anthranilic acid derivative;100 a structurally related to diclofenac and mefenamic acid.100 a

Uses for Meclofenamate

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 meclofenamate sodium therapy as well as alternative therapies before initiating therapy with the drug.100 146 Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.100 146

Inflammatory Diseases

Symptomatic treatment of acute and chronic osteoarthritis and rheumatoid arthritis.100 a

Has been used with some success in a limited number of adults with ankylosing spondylitis†a b or acute gouty arthritis†.a c

Has been used in a limited number of patients with psoriatic arthritis†.a

Pain

Relief of mild to moderate pain in adults.a 100 101 102 103 104 105 106

Dysmenorrhea and Menorrhagia

Treatment of primary dysmenorrhea.100 107 a

Treatment of idiopathic menorrhagia.100 112 a Use only for heavy menstrual flow that is idiopathic (i.e., no underlying pathophysiologic cause can be identified);100 112 do not use for the management of spotting or bleeding that occurs between menstrual cycles.100

Use for primary dysmenorrhea or idiopathic menorrhagia only when the potential benefits justify the possible risks.100

Meclofenamate Dosage and Administration

General

  • Consider potential benefits and risks of meclofenamate sodium therapy as well as alternative therapies before initiating therapy with the drug.100 146

Administration

Oral Administration

Administer orally.100 a

Administration with meal, milk, or antacids may minimize adverse GI effects.100 146 a

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 meclofenamate sodium; dosage expressed in terms of meclofenamic acid.100 a

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.100 146 a Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.100 146 a

Adults

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

200–400 mg daily in 3 or 4 equally divided doses.100 a Initiate at lower dosage and adjust dose and frequency as necessary based on severity of symptoms and clinical response (maximum 400 mg daily).100 146 a

Pain
Oral

50 mg every 4–6 hours.a 100 101 103 104 105 106 Some patients may require 100-mg doses for optimal pain relief (maximum 400 mg daily).a 100 101 102 103 104 105 106

Dysmenorrhea and Menorrhagia
Oral

100 mg 3 times daily.a 100 107 112 Initiated at onset of menses and continue ≤ 6 days or until cessation of menses.100 112 a

Prescribing Limits

Adults

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

Maximum 400 mg daily.100 a

Pain
Oral

For mild to moderate pain, maximum 400 mg daily.100 101

Dysmenorrhea and Menorrhagia
Oral

Maximum 300 mg daily.100

Special Populations

Renal Impairment

Dosage reduction recommended in patients with renal impairment; monitor renal function.100 a

Use not recommended in patients with advanced renal disease.146

Geriatric Patients

Consider reduced initial dosage; monitor carefully.a 100

Cautions for Meclofenamate

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.

  • Known hypersensitivity to meclofenamate sodium or any ingredient in the formulation.100 146 a

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.100 146 a

  • 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.150 151 152 154 500 501 502 503 506 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 dosage for the shortest duration necessary.146 500 508

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.146 147 502 508 (See Specific Drugs under Interactions.)

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms;100 108 109 117 146 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.100 146 a

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;111 120 134 135 alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole) or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).111 120 134

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.146 Use with caution in patients with hypertension; monitor BP.146

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.146 508 509 (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.146 508

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 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.100 146

Potential for overt renal decompensation.100 146 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.100 146 149 a (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.146

Immediate medical intervention and discontinuance for anaphylaxis.146

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.100 146

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported;100 146 can occur without warning.146 Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).146

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.100 146 a

Elevations of serum ALT, AST, or alkaline phosphatase reported.100 146

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.100 146 a Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.100 146 a

Hematologic Effects

Anemia reported.100 146 a Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.100 146 a

Leukopenia, thrombocytopenic purpura, neutropenia, and agranulocytosis reported rarely.100 a Decreased WBC counts usually transient and return to normal despite continued meclofenamate sodium therapy.100 a Further clinical evaluations are necessary if leukopenia, granulocytopenia, or thrombocytopenia persists; discontinuance of meclofenamate sodium therapy may be necessary.100 a

May inhibit platelet aggregation and prolong bleeding time.a 146

Ocular Effects

Ocular toxicity reported in patients receiving NSAIA therapy.100 a If visual difficulties develop during therapy, discontinue the drug and perform complete ophthalmologic examination.100 a

Sodium Content and Electrolyte Imbalance

100-mg meclofenamate sodium capsules each contain 0.34 mEq of sodium.a

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.146 a

May mask certain signs of infection or other conditions.146 a

Obtain CBC and chemistry profile periodically during long-term therapy.146 a

Specific Populations

Pregnancy

No FDA category rating.100 Safety not established; avoid use, particularly during first and third trimesters.100 146 a Avoid use in third trimester because of possible premature closure of the ductus arteriosus.a

Lactation

Meclofenamic acid is distributed into milk.a 100 Discontinue nursing or the drug.100 146 a

Pediatric Use

Safety and efficacy not established in children <14 years of age.100 a

Geriatric Use

Use with caution in patients ≥65 years of age.100 146 a Geriatric adults appear to tolerate NSAIA-induced adverse effects less well than younger individuals.a 100 146 Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.a 100

Renal Impairment

Metabolites eliminated principally via the kidney.100 a

Use with caution and close monitoring in patients with substantial renal impairment.100 a Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.146

Common Adverse Effects

Diarrhea, nausea with or without vomiting, other GI disorders, abdominal pain, flatulence, pyrosis, dizziness, headache, rash.100 146 a

Interactions for Meclofenamate

Protein-bound Drugs

Possible pharmacokinetic interaction; observe for adverse effects if used with other protein-bound drugs.100 a

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor possible146 153

Possible deterioration of renal function in individuals with renal impairment146

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist possible146 153

Possible deterioration of renal function in individuals with renal impairment146

Antacids (aluminum- and magnesium-containing)

No effect on meclofenamate sodium absorption100

Aspirin

May decrease plasma concentrations of meclofenamic acid100 a

Increased risk of GI ulceration and other complications100 137

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs147 502 508

Concomitant use not recommended146

Diuretics (furosemide, thiazides)

Reduced natriuretic effects146

Monitor for diuretic efficacy and renal failure146

Lithium

Increased plasma lithium concentrations146

Monitor for lithium toxicity146

Methotrexate

Possible toxicity associated with increased plasma methotrexate concentrations146

Caution advised146

Propoxyphene

Pharmacokinetic interaction unlikely100

Warfarin

Possible bleeding complications and increases in PT100 146 a

Monitor PT, adjust warfarin dosage as needed, and observe for adverse effects100 146 a

Meclofenamate Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed following oral administration.100 a Peak plasma concentrations usually attained within 0.5–2 hours following oral administration.2 100

Food

Food decreases rate27 100 and extent100 of absorption.

Distribution

Extent

Distribution into human body tissues and fluids not fully characterized.a In animals, the drug is distributed mainly into the plasma, liver, and kidneys, with lower concentrations being distributed into the heart, spleen, fat, skeletal muscle, and brain.a

Crosses the placenta.100 a Meclofenamic acid is distributed into milk.100 a

Plasma Protein Binding

>99% (mainly albumin).2 100 114 a

Elimination

Elimination Route

Excreted in urine (70%), mainly as glucuronide conjugates of the metabolites,2 27 100 114 and in feces (20–30%).2 27 100

Half-life

40 minutes–5.3 hours.2 100 114

Stability

Storage

Oral

Capsules

Tight, light-resistant containers at 15–30°C.100 a

Actions

  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.127 128 129 130 131 132

  • Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.100 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 each time the drug is dispensed.146

  • Risk of serious cardiovascular events (e.g., MI, stroke).146 150 151 152 154 500 508 Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.146 500 508

  • Risk of GI bleeding and ulceration.100 108 109 146 Importance of notifying a clinician if signs and symptoms of serious adverse GI effects occur.146

  • Risk of serious skin reactions.146 Importance of discontinuing meclofenamate sodium and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.146

  • Risk of anaphylactoid and other sensitivity reactions.146 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.146

  • Risk of hepatotoxicity.100 146 a Importance of discontinuing therapy and contacting a clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.146

  • Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.100 146 508

  • Risk of dizziness and potential for drug to impair mental alertness; use caution when driving or operating machinery until effects on individual are known.a

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.146 Importance of avoiding meclofenamate sodium in pregnancy, particularly during early and late pregnancy (first and third trimesters).100 146 a

  • Importance of advising women receiving meclofenamate sodium for menorrhagia to notify clinician if spotting or bleeding between menstrual cycles or worsening of menstrual blood flow occurs.100 a

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.100

  • Importance of informing patients of other important precautionary information.100 (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

Meclofenamate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg (of meclofenamic acid)*

Meclofenamate Sodium Capsules

100 mg (of meclofenamic acid)*

Meclofenamate Sodium Capsules

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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