Cardiovascular Effects 
Congestive heart failure,125 hypertension,125 tachycardia,125 syncope,125 arrhythmia,125 hypotension,125 myocardial infarction,125 palpitations,125 and vasculitis125 have occurred in mefenamic acid-treated patients.125
Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500,502,508 Use of NSAIAs also is associated with an increased risk of heart failure.500,508
The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.129,136,500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in 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 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, 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
Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.505,508 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).500,508,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.508,511
In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.508 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.508
Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.133,134,135,136,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)
Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.500,504,507,508 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.500,504,508 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.500,501,508 Fluid retention and edema also have been observed in some patients receiving NSAIAs.508
There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.125,502,508
GI Effects
Adverse reactions to mefenamic acid mainly involve the GI tract and may include diarrhea, nausea with or without vomiting, abdominal pain, dyspepsia, heartburn, flatulence, constipation, gross bleeding/GI perforation, and peptic ulcer with or without bleeding. Dry mouth,125 esophagitis,125 gastritis,125 glossitis,125 stomatitis,125 weight changes,125 appetite changes,125 eructation,125 and hematemesis125 have occurred in patients receiving mefenamic acid.125
Adverse GI effects may be minimized by administering mefenamic acid with food. In one study, the amount of GI bleeding as determined by fecal blood loss was reported to be less with 2 g of mefenamic acid daily than with 2.6 g of aspirin daily. Although a causal relationship has not been directly determined, one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.
Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.100,101,104,125 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.125 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up.100,101,125 In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.100,101 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.125
Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.100,101 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.100,101 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.125 However, short-term therapy is not without risk.125 High dosages of any NSAIA probably are associated with an increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.100,101 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.100,101
Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors.124,126 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant administration of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status.124,125,126,128 Most spontaneous reports of fatal GI effects have been in geriatric or debilitated patients.125
For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.124,127 (See Misoprostol 56:28.28.) Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.124
Hematologic Effects
The most common adverse hematologic effect of mefenamic acid is a decrease in hematocrit, principally in patients who have received the drug for prolonged periods. Leukopenia, eosinophilia,125 agranulocytosis,125 pancytopenia,125 ecchymosis, 125 melena,125 purpura, 125 rectal bleeding,125 thrombocytopenia,125 hemolytic anemia, 125 aplastic anemia, 125 and lymphadenopathy125 have also been reported occasionally.125 Since mefenamic acid can inhibit platelet aggregation, patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during mefenamic acid therapy.
Nervous System Effects
Adverse nervous system effects occur occasionally in patients receiving mefenamic acid and may include drowsiness,125 dizziness,125 nervousness125 , headache,125 anxiety,125 asthenia,125 confusion,125 depression,125 dream abnormalities,125 malaise,125 paresthesia,125 somnolence,125 tremors,125 vertigo,125 and insomnia.125 Seizures,125 coma,125 hallucinations,125 or meningitis125 has occurred rarely in patient receiving mefenamic acid.125
Ocular and Otic Effects
Blurred vision, 125 tinnitus,125 conjunctivitis,125 and hearing impairment125 have occurred in patients receiving mefenamic acid. Patients who experience visual disturbances during therapy with the drug should have an ophthalmologic examination.
Renal Effects
Abnormal renal function,125 edema,125 cystitis,125 dysuria,125 hematuria,125 interstitial nephritis,125 oliguria/polyuria,125 proteinuria,125 and renal failure125 have been reported in mefenamic acid-treated patients.125 Long-term mefenamic acid therapy has resulted in renal papillary necrosis and other renal medullary changes.125
Hepatic Effects
Mild hepatotoxicity has been reported during mefenamic acid therapy. Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in less than 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Hepatitis,125 jaundice,125 and liver failure125 have been reported in patients receiving mefenamic acid.125 Mefenamic acid should be discontinued if signs or symptoms of a severe hepatic reaction occur. (See Cautions: Precautions and Contraindications.)
Other Adverse Effects
Urticaria,125 rash, 125 pruritus,125 alopecia,125 photosensitivity,125 and perspiration125 have been reported following mefenamic acid administration. Rarely reported adverse effects include death,125 angioedema,125 anaphylactoid reactions,125 toxic epidermal necrosis,125 erythema multiforme,125 exfoliative dermatitis,125 and Stevens-Johnson syndrome.125
Asthma,125 dyspnea,125 respiratory depression,125 and pneumonia125 have been reported in patients receiving mefenamic acid.125 Other adverse effects reported in these patients include fever,125 infection,125 sepsis,125 hyperglycemia,125 and pancreatitis.125
Precautions and Contraindications
Patients should be advised that mefenamic acid, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.100,101,125,500,508 Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases, and the drugs have a major role in the management of pain.100,101 Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.100,101
Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.125
NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.125,133,134,135,136,500,502,508 (See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.125,500,508 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.125,500,508 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.125,500,508 Mefenamic acid should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if mefenamic acid is used in such patients, the patient should be monitored for cardiac ischemia.508
There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.125,129,502,508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.125 Because of the potential for increased adverse effects, patients receiving mefenamic acid should be advised not to take aspirin.125
Use of NSAIAs can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.125 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.125,508 NSAIAs should be used with caution in patients with hypertension.125 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.125
Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that mefenamic acid should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if mefenamic acid is used in such patients, the patient should be monitored for worsening heart failure.508 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.508 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).508 (See Drug Interactions.)
The risk of potentially serious adverse GI effects should be considered in patients receiving mefenamic acid, particularly in patients receiving chronic therapy with the drug.100,101,125 (See Cautions: GI Effects.) Mefenamic acid should be used with caution in patients with a history of upper GI disease.125 Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.125
Mefenamic acid should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration,125 and such patients should receive an appropriate ulcer preventive regimen.109,114,115,116,124,127 All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs and symptoms of ulcer perforation or GI bleeding.109,114,115,116,125 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed.128 For patients who are at high risk, therapy other than an NSAIA should be considered.125 The manufacturer states that mefenamic acid is contraindicated in patients with active ulceration or chronic inflammation of the upper or lower GI tract.
The possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mask the usual signs and symptoms of infection or other diseases should be considered.125
Elevations in serum ALT may be the most sensitive indicator of NSAIA-induced liver dysfunction. Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving mefenamic acid should be evaluated for evidence of the development of a severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs. Although such reactions are rare, mefenamic acid should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).
Patients receiving mefenamic acid are at risk of developing adverse renal effects.125 Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.125 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.125 Patients at greatest risk of this reaction include those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II receptor antagonist concomitantly; and geriatric patients.125,131 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.125 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.125
The manufacturer states that mefenamic acid should not be administered to patients with substantial renal impairment.125
Mefenamic acid is not a substitute for corticosteroid therapy.125 Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration, and the drugs should be used concomitantly with caution.107,112 If corticosteroid dosage is decreased during mefenamic acid therapy, it should be done gradually and patients should be observed for adverse effects, including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.125
Mefenamic acid should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), because the drug may inhibit platelet function.125 If signs and/or symptoms of anemia occur during therapy with mefenamic acid, hemoglobin concentration and hematocrit should be determined.125
Anaphylactoid reactions have been reported in patients receiving mefenamic acid.125 Patients receiving mefenamic acid should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.125
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.125 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.125 Mefenamic acid should be discontinued at the first appearance of rash or any other sign of hypersensitivity.125
Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.1202 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1202 Symptoms may resemble those of an acute viral infection.1202 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1202 If such signs or symptoms develop, the NSAIA should be discontinued and the patient evaluated immediately.1202
Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.125
The manufacturers state that mefenamic acid is contraindicated in patients with known hypersensitivity to the drug.125 In addition, NSAIAs generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients.125 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, NSAIAs should be used with caution in patients with asthma.125 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.125 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24
NSAIAs are contraindicated in the setting of CABG surgery.508
Pediatric Precautions
Safety and efficacy of mefenamic acid in children younger than 14 years of age have not been established.125
Geriatric Precautions
Caution should be observed if mefenamic acid is used in geriatric individuals.125 Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.125 (See Cautions: GI Effects.)
Clinical studies of mefenamic acid did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger individuals.125
Because geriatric patients are more likely to have decreased renal function and patients with renal impairment may be at increased risk of adverse reactions to mefenamic acid, the dosage should be selected carefully.125 It may be useful to monitor renal function in geriatric patients.125
Pregnancy, Fertility, and Lactation
Pregnancy
Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.1200,1202 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.1200,1202 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.1200,1202 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.1200,1202
Known effects of NSAIAs on the human fetus during the 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
Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.1200,1202 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200,1202 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200,1202 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200,1202 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1200,1202 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.1202 These limitations preclude establishing 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, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.1202
Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.1201 In animal studies, inhibitors of prostaglandin synthesis, such as mefenamic acid, were associated with increased pre- and post-implantation losses.1201 Prostaglandins also have an important role in fetal kidney development.1202 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1202
There are no adequate and well-controlled studies of mefenamic acid in pregnant women.1201 Animal reproduction studies in rats and rabbits revealed no evidence of developmental effects at mefenamic acid dosages of 1.6 and 0.6 times, respectively, the maximum recommended human dosage (MRHD); administration of the drug at a dosage of 1.2 times the MRHD from gestation day 15 to weaning or at a dosage equivalent to the MRHD from 15 days prior to mating through weaning resulted in an increased incidence of perinatal deaths.1201
The effects of mefenamic acid on labor and delivery are unknown.1201 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, increased the incidence of dystocia, delayed parturition, decreased pup survival, and increased the incidence of stillbirth.1201
Fertility
Use of NSAIAs, including mefenamic acid, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1201 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.1201 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1201
Doses of mefenamic acid up to 10 times the usual human dose have resulted in decreased fertility in rats.
Lactation
Mefenamic acid is distributed into milk. Because of the potential for adverse effects from mefenamic acid on the cardiovascular system in infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Laboratory Test Interferences
Mefenamic acid may cause a false-positive reaction for urinary bile using the diazo tablet test. If biliuria is suspected, the finding should be confirmed by other diagnostic tests (e.g., Harrison spot test).
Acute Toxicity
Limited information is available on the acute toxicity of mefenamic acid.
Manifestations
Coma and tonic-clonic seizures (which resolved following treatment with IV diazepam) occurred following ingestion of 5-10 g of mefenamic acid by a 13-year-old girl. Acute ingestion of large doses of mefenamic acid in animals has led to incoordination, depression, tonic seizures, and diarrhea.
In humans who reportedly ingested 1.5-50 g of mefenamic acid, those with plasma drug concentrations ranging from 11-211 mcg/mL experienced tonic-clonic seizures, muscle twitching, vomiting, and diarrhea. Several other cases of seizures following ingestion of 5-50 g of mefenamic acid have also been reported, although a causal relationship to the drug was not established.
Treatment
In acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage, followed by administration of activated charcoal. Forced diuresis, alkalinization of urine, or hemodialysis are probably of no value in enhancing elimination of mefenamic acid since the drug is highly bound to plasma proteins.
Pharmacology
Mefenamic acid has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis. Mefenamic acid inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.117,118,119,120,121,122 Mefenamic acid, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.117,118,119,120,121,122 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.117,118,119,120,121,122 Unlike most other NSAIAs, the fenamates, including mefenamic acid, appear to compete with prostaglandins for binding at the prostaglandin receptor site and thus potentially affect prostaglandins that have already been formed.
Anti-inflammatory, Analgesic, and Antipyretic Effects
The anti-inflammatory, analgesic, and antipyretic effects of mefenamic acid and other NSAIAs, including selective inhibitors of COX-2 (e.g., celecoxib), appear to result from inhibition of prostaglandin synthesis. While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.117,118,119,120,121,122
Mefenamic acid also has been reported to inhibit the biosynthesis of mucopolysaccharides through uncoupling of oxidative phosphorylation, a mechanism that may also contribute to the anti-inflammatory effect of the drug. Mefenamic acid does not possess glucocorticoid or adrenocorticoid-stimulating properties.
There is no evidence that long-term therapy with mefenamic acid results in tolerance to or physical dependence on the drug. The drug probably cannot suppress the abstinence syndrome in opiate-dependent patients.
Mefenamic acid lowers body temperature in patients with fever. Although the mechanism of the antipyretic effect of NSAIAs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.
Genitourinary and Renal Effects
Mefenamic acid-induced inhibition of prostaglandin synthesis may result in decreased uterine tone and contractility. Prostaglandins E2 and F2α increase the amplitude and frequency of uterine contractions in pregnant women; current evidence suggests that primary dysmenorrhea is also mediated by these prostaglandins. Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined.123 In some patients with primary dysmenorrhea, mefenamic acid has produced an analgesic effect. Therapy with mefenamic acid has been effective in relieving menstrual pain and has also reduced blood loss in women with menorrhagia, probably by inhibiting the formation and/or action of these prostaglandins. Administration of mefenamic acid during late pregnancy may prolong gestation by inhibiting uterine contractions.
Mefenamic acid has been reported to adversely affect renal function. (See Cautions: Renal Effects.) Very little is known about the mechanisms of adverse renal effects, although it has been suggested that papillary necrosis observed during therapy with mefenamic acid may be related to a reduction in renal blood flow resulting from the inhibition of renal prostaglandin synthesis.
Mefenamic acid does not appear to have uricosuric activity.
GI Effects
Mefenamic acid can cause gastric mucosal damage which may result in ulceration and/or bleeding. (See Cautions: GI Effects.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.117,118,119,120,121,122,124 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.119,124
Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.121 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to be determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.121
Hematologic Effects
Mefenamic acid can inhibit platelet aggregation; in one study, the drug inhibited the platelet aggregation response induced by connective tissue particles. Like aspirin and other prototypical NSAIAs, the effects of mefenamic acid on platelets appear to be associated with the inhibition of the synthesis of prostaglandins produced by COX-1.121
Pharmacokinetics
Absorption
Mefenamic acid appears to be rapidly absorbed from the GI tract. Following oral administration of a single 1-g dose of mefenamic acid to healthy adults, peak plasma drug concentrations of approximately 10-20 mcg/mL are reached in 2-4 hours. Following oral administration of 1 g of mefenamic acid 4 times daily, steady-state concentrations of 20 mcg/mL are reached by the second day of administration. After multiple doses, plasma concentrations of mefenamic acid are 15proportional to the dose administered. The manufacturer states that there is no evidence of drug accumulation following multiple doses.
Distribution
Mefenamic acid is extensively bound to plasma proteins. It is not known if the drug or its metabolites cross the placenta. The drug is distributed into milk in very small amounts.
Elimination
The plasma half-life of mefenamic acid has been reported to be 2 hours.
Mefenamic acid is metabolized by cytochrome P-450 (CYP) isoenzyme 2C9 to 3'-hydroxymethyl mefenamic acid; further oxidation to 3'-carboxylmefenamic acid may occur.125 Glucuronic acid conjugates of the drug and its metabolites are also formed.
About 52% of a dose of mefenamic acid is excreted in urine as glucuronic acid conjugates of the drug and its metabolites. About 20% of a dose is excreted in feces. Mefenamic acid is apparently not dialyzable.
Chemistry and Stability
Chemistry
Mefenamic acid, an anthranilic acid derivative (fenamate), is a prototypical nonsteroidal anti-inflammatory agent (NSAIA). The drug is structurally and pharmacologically related to meclofenamate sodium. Mefenamic acid occurs as a white to greyish-white powder and is insoluble in water and slightly soluble in alcohol. The apparent pKa of the drug is 4.2.
Stability
Mefenamic acid capsules should be stored at a controlled room temperature of 20-25°C, but may be exposed to temperatures ranging from 15-30°C.125
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.
Only references cited for selected revisions after 1984 are available electronically.
100. Palmer JF. Letter sent to Lents CE, of Parke Davis, Division of Warner-Lambert Company regarding labeling revisions about gastrointestinal adverse reactions to Ponstel® (mefenamic acid). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products. 1988 Sep.
101. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull . 1989; 19:3-4.
102. Searle. Cytotec® (misoprostol) prescribing information. Skokie, IL; 1989 Jan.
104. Soll AH, Weinstein WM, Kurata J et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med . 1991; 114:307-19. [PubMed 1987878]
105. Nonsteroidal anti-inflammatory drug interactions: Lithium. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:608-9.
106. Miller LG, Bowman RC, Bakht F. Sparing effect of sulindac on lithium levels. J Fam Prac . 1989; 28:592-3.
107. Corticosteroid interactions: nonsteroidal anti-inflammatory drugs (NSAIDs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:562.
108. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet . 1994; 343:769-72. [PubMed 7907735]
109. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med . 1994; 96:274-81. [PubMed 8154516]
110. Schubert TT, Bologna SD, Yawer N et al. Ulcer risk factors: interaction between Helicobacter pylori infection, nonsteroidal use, and age. Am J Med . 1993; 94:413-7. [PubMed 8475935]
111. Bateman DN, Kennedy JG. Non-steroidal anti-inflammatory drugs and elderly patients: the medicine may be worse than the disease. BMJ . 1995; 310:817-8. [PubMed 7711609][PubMedCentral]
112. Piper JM, Ray WA, Daugherty JR et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med . 1991; 114:735-40. [PubMed 2012355]
113. Lithium interactions: diclofenac. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:607.
114. Ciba Geigy, Ardsley, NY: Personal communication on diclofenac 28:08.04.
115. Reviewers' comments (personal observations) on diclofenac 28:08.04.
116. Searle. Cytotec® (misoprostol) prescribing information. 1989 Jan.
117. Hawkey CJ. COX-2 inhibitors. Lancet . 1999; 353:307-14. [PubMed 9929039]
118. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature . 1996; 384:644-8. [PubMed 8967954]
119. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmaco . 1997; 75:1088-95.
120. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med Chem Res . 1995; 5:325-43.
121. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Other Lipid Mediators . 1998; 56:341-61. [PubMed 9990677]
122. Simon LS, Role and regulation of cyclooxygenase-2 during inflammation. Am J Med . 1999; 106(Suppl 5B):37-42S.
123. Morrison BW, Daniels SE, Kotey P et al. Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: a randomized controlled study. Obstet Gynecol . 1999; 94:504-8. [PubMed 10511349]
124. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med . 1999; 340:1888-99. [PubMed 10369853]
125. First Horizon. Ponstel® (mefenamic acid) capsules prescribing information. Alpharetta, GA; 2006 Jan.
126. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol . 1999; 26(suppl 56):18-24.
127. Lanza FL, and the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol . 1998; 93:2037-46. [PubMed 9820370]
128. Merck & Co. Clinoril® (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.
129. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.
130. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website ([Web]). Accessed 2005 Oct 12.
131. Novartis Pharmaceuticals. Diovan® (valsartan) capsules prescribing information (dated 1997 Apr). In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.
132. Pharmacia. Daypro® (oxaprozin) caplets prescribing information. Chicago, IL; 2002 May.
133. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA . 2006; 296: 1633-44. [PubMed 16968831]
134. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ . 2006; 332: 1302-5. [PubMed 16740558][PubMedCentral]
135. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA . 2006; 296:1653-6. [PubMed 16968830]
136. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at: [Web].
500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD; 2015 Jul 9. From the FDA web site. Accessed 2016 Mar 22. [Web]
501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet . 2013; 382:769-79. [PubMed 23726390][PubMedCentral]
502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site [Web]
503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ . 2011; 342:c7086. [PubMed 21224324][PubMedCentral]
504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med . 2009; 169:141-9. [PubMed 19171810]
505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation . 2011; 123:2226-35. [PubMed 21555710]
506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med . 2011; 8:e1001098. [PubMed 21980265][PubMedCentral]
507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol . 2013; 62:e147-239. [PubMed 23747642]
508. Lupin. Mefenamic acid capsules prescribing information. Baltimore, MD; 2016 Jun.
511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation . 2012; 126:1955-63. [PubMed 22965337]
512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One . 2013; 8:e54309.
516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med . 2011; 124:614-20. [PubMed 21596367][PubMedCentral]
1200. US Food and Drug Administration. FDA drug safety communication: FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. 2020 Oct 15. From the FDA website. [Web]
1201. Micro Labs USA. Mefenamic acid capsules prescribing information. Basking Ridge, NJ; 2020 Jan.
1202. Actavis Pharma. Sulindac tablets prescribing information. Parsippany, NJ; 2020 Oct.