Drug class: Other Nonsteroidal Anti-inflammatory Agents
- NSAIAs
- NSAIDs
VA class: MS120
Chemical name: N-(2,3-xylyl)anthranilic acid
Molecular formula: C₁₅H₁₅NO₂
CAS number: 61-68-7

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Introduction

Prototypical NSAIA; anthranilic acid derivative (fenamate); structurally and pharmacologically related to meclofenamate sodium.^{125 a}

Uses for Mefenamic Acid

Consider potential benefits and risks of mefenamic acid therapy as well as alternative therapies before initiating therapy with the drug.^{125 b} Use lowest possible effective dosage and shortest duration of therapy consistent with patient’s treatment goals.^{125 b}

Pain

Relief of mild to moderate pain in patients ≥14 years of age when the duration of therapy ≤1 week.^{125 b}

Dysmenorrhea

Treatment of primary dysmenorrhea.^{125 b}

Fever

Has been used for reduction of fever^{† [off-label]} associated with infection in children; routine use as an antipyretic not recommended because of potential adverse effects.^a

Mefenamic Acid Dosage and Administration

General

• Consider potential benefits and risks of mefenamic acid therapy as well as alternative therapies before initiating therapy with the drug.^{125 b}

Administration

Oral Administration

Administer orally.¹²⁵ May be administered in divided doses up to 4 times daily.¹²⁵

Dosage

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.^{125 b} Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{125 b}

Pediatric Patients

Pain

Oral

Adolescents ≥14 years of age should receive dosage recommended for adults.¹²⁵ (See Adult Dosage.)

Adults

Pain

Oral

For mild to moderate pain in adults, 500 mg initially followed by 250 mg every 6 hours as necessary.¹²⁵

Dysmenorrhea

Oral

For relief of primary dysmenorrhea in adults, 500 mg initially followed by 250 mg every 6 hours as necessary.¹²⁵ Initiate at onset of bleeding and associated symptoms; treatment should not be necessary for >2–3 days.¹²⁵

Prescribing Limits

Pediatric Patients

Pain

Oral

Duration of therapy usually should not exceed 1 week.¹²⁵

Adults

Pain

Oral

Duration of therapy usually should not exceed 1 week.¹²⁵

Dysmenorrhea

Oral

Therapy should not be necessary for more than 2–3 days.¹²⁵

Special Populations

Hepatic Impairment

Dosage reduction may be required.¹²⁵

Renal Impairment

Dosage reduction may be required if used in patients with renal impairment.¹²⁵

Use not recommended in patients with preexisting renal disease or substantial renal impairment.¹²⁵

Geriatric Patients

Select dosage carefully since may be more likely to have decreased renal function.^{125 b}

Related/similar drugs

acetaminophen, ibuprofen, cyclobenzaprine, tramadol, naproxen, diclofenac, oxycodone

Cautions for Mefenamic Acid

Contraindications

• Known hypersensitivity to mefenamic acid or any ingredient in the formulation.^{125 b}

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{125 b}

• In the setting of CABG surgery.⁵⁰⁸

• Active ulceration or chronic inflammation of upper or lower GI tract.¹²⁵

• Preexisting renal disease.¹²⁵

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 information^{500 501 502} 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.^{133 134 135 136 500 501 502 503 506} 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.^{125 500 508 b}

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.^{125 502 508 b} (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.^{100 104 124 125 126 b}

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{124 127 h i} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{124 h i} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).^{125 h}

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^{125 b} Use with caution in patients with hypertension; monitor BP.^{125 b}

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.^{125 508 b} (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.^{125 508 b}

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.^{125 b}

Potential for overt renal decompensation.^{125 b} 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.^{125 128 b} (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.^{125 b} Immediate medical intervention and discontinuance for anaphylaxis.^{125 b}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.^{125 b}

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.¹²⁰² 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).¹²⁰² Symptoms may resemble those of acute viral infection.¹²⁰² Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.¹²⁰² If signs or symptoms of DRESS develop, discontinue the NSAIA and immediately evaluate the patient.¹²⁰²

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.^{125 b} Discontinue at first appearance of rash or any other signs of hypersensitivity (e.g., blisters, fever, pruritus).^{125 b}

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.^{125 b}

Elevations of serum ALT or AST reported.^{125 b}

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^{125 b} Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.^{125 b}

Hematologic Effects

Anemia reported rarely.^{125 b} Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.^{125 b}

May inhibit platelet aggregation and prolong bleeding time.^{125 b}

Ocular Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.^{125 a}

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.^{125 b}

May mask certain signs of infection.^{125 b}

Obtain CBC and chemistry profile periodically during long-term use.^{125 b}

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.^{1200 1202}

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.¹²⁰²

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.^{1200 1202} (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.^{1200 1202} Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.^{1200 1202} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{1200 1202} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{1200 1202} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{1200 1202} Deaths associated with neonatal renal failure also reported.¹²⁰⁰ 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.¹²⁰² Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.¹²⁰²

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.¹²⁰¹ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.¹²⁰¹

No adequate and well-controlled studies of mefenamic acid in pregnant women.¹²⁰¹ Increased incidence of perinatal deaths observed in animal studies; no evidence of developmental effects.¹²⁰¹

Effects of mefenamic acid on labor and delivery not known.¹²⁰¹ In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, decreased pup survival, and increased stillbirths.¹²⁰¹

Lactation

Distributed into milk.^{125 c} Discontinue nursing or the drug.¹²⁵

Fertility

NSAIAs may be associated with reversible infertility in some women.¹²⁰¹ 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.¹²⁰¹

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.¹²⁰¹

Pediatric Use

Safety and efficacy not established in children <14 years of age.¹²⁵

Geriatric Use

Use with caution in patients ≥65 years of age.^{125 b} Geriatric adults appear to tolerate therapy less well (e.g., possible higher incidence of adverse GI effects, greater risk of developing renal decompensation) than younger individuals.^{125 b} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{125 b}

Substantially eliminated by kidneys; periodic monitoring of renal function may be useful since geriatric patients are more likely to have decreased renal function.¹²⁵ (See Geriatric Patients under Dosage and Administration and Renal Impairment under Cautions.)

Renal Impairment

Use not recommended in patients with preexisting renal disease or substantial renal impairment.¹²⁵

Common Adverse Effects

Abdominal pain,¹²⁵ constipation,¹²⁵ diarrhea,¹²⁵ dyspepsia,¹²⁵ flatulence,¹²⁵ gross bleeding/perforation,¹²⁵ heartburn,¹²⁵ nausea,¹²⁵ GI ulcers (gastric/duodenal),¹²⁵ vomiting,¹²⁵ abnormal renal function,¹²⁵ anemia,¹²⁵ dizziness,¹²⁵ edema,¹²⁵ elevated liver enzymes,¹²⁵ headaches,¹²⁵ increased bleeding time,¹²⁵ pruritus,¹²⁵ rashes,¹²⁵ tinnitus.¹²⁵

Drug Interactions

Protein-bound Drugs

Possible pharmacokinetic interaction; potential for mefenamic acid to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs (e.g., oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas).^{125 a f} Observe for adverse effects if used with other protein-bound drugs.^a

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2C9: possible altered safety and efficacy of mefenamic acid.¹²⁵

Specific Drugs

Mefenamic Acid Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration.^{125 a} Peak plasma concentrations usually attained within 2–4 hours.^{125 a}

Food

Effect of food on rate and extent of absorption not known.¹²⁵

Distribution

Extent

Appears to cross the placenta.^g

Distributed into milk in small amounts.^{125 c}

Plasma Protein Binding

>90%.¹²⁵

Elimination

Metabolism

Metabolized by CYP2C9 to 3′-hydroxymethyl mefenamic acid; further oxidation to 3′-carboxymefenamic acid may occur. ¹²⁵ Mefenamic acid and its metabolites also are glucuronidated.¹²⁵

Elimination Route

Excreted in urine (52%) primarily as glucuronic acid conjugates of the drug and its metabolites and in feces (<20%).¹²⁵

Half-life

Mefenamic acid: approximately 2 hours.¹²⁵ Half-lives of 3′-hydroxymethyl mefenamic acid and 3′-carboxymefenamic acid may be longer than parent compound.¹²⁵

Special Populations

Half-life 5 times longer in preterm infants compared with adults.¹²⁵

In patients with renal or hepatic impairment, clearance of metabolites may be decreased.¹²⁵

Not substantially removed by hemodialysis.^{125 a}

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).^{125 a}

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{117 118 119 120 121 122}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{125 a}

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.^{125 b}

• Risk of serious cardiovascular events (e.g., MI, stroke).^{125 500 508 b} Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^{125 500 508 b}

• Risk of GI bleeding and ulceration.^{100 104 125 b} Importance of notifying a clinician if signs and symptoms of serious adverse GI effects occur.^{125 b}

• Risk of serious skin reactions, DRESS, and anaphylactoid and other sensitivity reactions.^{1201 1202} Advise patients to stop taking the drug immediately if they develop any type of rash or fever and to promptly contact their clinician.¹²⁰² Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{125 b}

• Risk of hepatotoxicity.^{125 b} 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.^{125 b}

• Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.^{125 508 b}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹²⁵

• 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.^{1200 1202}

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.¹²⁰¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹²⁵

• Importance of informing patients of other important precautionary information.¹²⁵ (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

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