Meclofenamate Sodium (Monograph)

Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

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

Uses for Meclofenamate Sodium

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

Inflammatory Diseases

Symptomatic treatment of acute and chronic osteoarthritis and rheumatoid arthritis.

Has been used with some success in a limited number of adults with ankylosing spondylitis^{† [off-label]} or acute gouty arthritis^{† [off-label]}.

Has been used in a limited number of patients with psoriatic arthritis^{† [off-label]}.

Pain

Relief of mild to moderate pain in adults.

Dysmenorrhea and Menorrhagia

Treatment of primary dysmenorrhea.

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

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

Meclofenamate Sodium Dosage and Administration

General

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

Administration

Oral Administration

Administer orally.

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

Dosage

Available as meclofenamate sodium; dosage expressed in terms of meclofenamic acid.

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

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

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

Pain

Oral

50 mg every 4–6 hours. Some patients may require 100-mg doses for optimal pain relief (maximum 400 mg daily).

Dysmenorrhea and Menorrhagia

Oral

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

Prescribing Limits

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Maximum 400 mg daily.

Pain

Oral

For mild to moderate pain, maximum 400 mg daily.

Dysmenorrhea and Menorrhagia

Oral

Maximum 300 mg daily.

Special Populations

Renal Impairment

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

Use not recommended in patients with advanced renal disease.

Geriatric Patients

Consider reduced initial dosage; monitor carefully.

Cautions for Meclofenamate Sodium

Contraindications

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

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

• In the setting of CABG surgery.

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.

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.

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.

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.

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.

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; 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.

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. FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.

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.

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease. 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. Contraindicated in the setting of CABG surgery.

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs. (See Specific Drugs 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.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol; 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).

Hypertension

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

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

Heart Failure and Edema

Fluid retention and edema reported.

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema. (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.

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.

Potential for overt renal decompensation. 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. (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported. Immediate medical intervention and discontinuance for anaphylaxis.

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

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs. Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Symptoms may resemble those of acute viral infection. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash. If signs or symptoms of DRESS develop, discontinue meclofenamate and immediately evaluate the patient.

Dermatologic Reactions

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

General Precautions

Hepatic Effects

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

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

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

Hematologic Effects

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

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

May inhibit platelet aggregation and prolong bleeding time.

Ocular Effects

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

Sodium Content and Electrolyte Imbalance

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

Other Precautions

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

May mask certain signs of infection or other conditions.

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

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice. (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs. Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios. Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis). Deaths associated with neonatal renal failure also reported. Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.

Animal studies revealed no evidence of developmental abnormalities with meclofenamate.

Effects of meclofenamate on labor and delivery not known. In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and decreased pup survival.

Lactation

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

Fertility

NSAIAs may be associated with reversible infertility in some women. Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.

Pediatric Use

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

Geriatric Use

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

Renal Impairment

Metabolites eliminated principally via the kidney.

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

Common Adverse Effects

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

Drug Interactions

Protein-bound Drugs

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

Specific Drugs

Meclofenamate Sodium Pharmacokinetics

Absorption

Bioavailability

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

Food

Food decreases rate and extent of absorption.

Distribution

Extent

Distribution into human body tissues and fluids not fully characterized. 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.

Crosses the placenta. Meclofenamic acid is distributed into milk.

Plasma Protein Binding

>99% (mainly albumin).

Elimination

Elimination Route

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

Half-life

40 minutes–5.3 hours.

Stability

Storage

Oral

Capsules

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

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.

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

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

• Risk of serious skin reactions, DRESS, and anaphylactoid and other sensitivity reactions. Advise patients to stop taking meclofenamate immediately if they develop any type of rash or fever and to promptly contact their clinician. Importance of seeking immediate medical attention if an anaphylactic reaction occurs.

• Risk of hepatotoxicity. 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.

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

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

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.

• 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.

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

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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

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