AHFS Class:

• Reversible COX-1/COX-2 Inhibitors 28:08.04.04

Generic Name(s):

• Meclofenamate Sodium

Meclofenamic acid is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and antipyretic activity.

Meclofenamate sodium is used for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis and osteoarthritis, for the relief of mild to moderate pain, for the symptomatic relief of primary dysmenorrhea, and for the management of idiopathic menorrhagia.

The potential benefits and risks of meclofenamate sodium therapy as well as alternative therapies should be considered prior to initiating meclofenamate sodium therapy.146 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.146

Inflammatory Diseases

Rheumatoid Arthritis and Osteoarthritis

Meclofenamate sodium is used in the symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis. Although meclofenamate sodium was previously believed to produce a relatively high incidence of adverse GI effects, including diarrhea, clinical experience indicates that the drug does not appear to be associated with a substantially greater risk of toxicity than most other NSAIAs.

When used in the treatment of rheumatoid arthritis or osteoarthritis, meclofenamate sodium has relieved pain and stiffness, and reduced swelling, tenderness, and the number of joints involved. The drug has also improved grip strength in patients with rheumatoid arthritis, and improved knee joint function in patients with osteoarthritis. Meclofenamate sodium appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. Safety and efficacy of the drug in patients who are incapacitated, largely or wholly bedridden, or confined to a wheelchair with little or no capacity for self-care (Functional Class IV rheumatoid arthritis) have not been established.

Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of meclofenamate sodium in the treatment of rheumatoid arthritis or osteoarthritis are greater than those of placebo and about equal to those of usual dosages of aspirin or indomethacin. Patient response to NSAIAs is variable; patients who do not respond to or cannot tolerate one drug might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs. (See Cautions: Precautions and Contraindications.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.111,120 Disease-modifying antirheumatic drugs (DMARDs) (e.g., abatacept, hydroxychloroquine, leflunomide, methotrexate, rituximab, sulfasalazine, tocilizumab, tofacitinib, tumor necrosis factor [TNF; TNF-α] blocking agents) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy.120 DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs.120 NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.111,120 (For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis, in Methotrexate 10:00)

Use of meclofenamate sodium with aspirin is not recommended. There is inadequate proof that the combination is more efficacious than either drug alone, the potential for adverse reactions may be increased, and there is some evidence that aspirin decreases plasma meclofenamic acid concentrations. (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Other Inflammatory Conditions

Meclofenamate sodium has been used in a limited number of patients in the symptomatic treatment of ankylosing spondylitis†. In one study, the anti-inflammatory and analgesic effects of usual dosages of meclofenamate sodium in the symptomatic treatment of ankylosing spondylitis were comparable to those of usual dosages of indomethacin. Meclofenamate sodium has also been used in the management of acute gouty arthritis†.

In a few patients with psoriatic arthritis†, meclofenamate sodium has relieved arthritic symptoms and therapy with the drug has resulted in regression (sometimes complete) of psoriatic signs and symptoms including regression of the lesions and decreased desquamation and itching. Further studies are required to determine the efficacy of the drug in the treatment of this condition.

Pain

Meclofenamate sodium is used for symptomatic relief of mild to moderate pain,100,101,102,103,104,105,106 such as postoperative (including that associated with dental surgery)101,102,103 and postpartum pain.104,105,106 When used to relieve mild to moderate acute pain, single meclofenamate doses of 100-200 mg of meclofenamic acid are more effective than placebo and at least as effective as usual analgesic doses of other NSAIAs or mild opiate analgesics (e.g., codeine).101,102,103,104,105,106 In patients with oral surgery pain, 100- to 200-mg doses of meclofenamic acid have been reported to be more effective than 600-mg doses of aspirin.101,102,103 In the management of episiotomy pain, the analgesic effect of 100- to 200-mg doses of the drug has been reported to be greater than that of 60-mg doses of oral codeine.104,105,106

Dysmenorrhea and Menorrhagia

Meclofenamate sodium is used for symptomatic relief of primary dysmenorrhea.100,107 and for the management of idiopathic menorrhagia (excessive uterine bleeding occurring at menstruation).100,112 Evidence from controlled studies in women with primary dysmenorrhea indicates that meclofenamate sodium therapy can provide symptomatic relief (as determined by subjective measures of pain intensity and relief) and reductions in intrauterine pressure and uterine activity.100,107 Evidence from controlled studies in women with idiopathic menorrhagia indicates that therapy with the drug can substantially reduce menstrual blood loss and provide symptomatic relief of associated dysmenorrhea, backache, and headache.110,112 Although the degree of blood flow reduction was variable, some degree of reduction occurred in about 90% of women in these studies.100,112 In addition, the duration of menses was decreased by about 1 day and tampon/sanitary pad use was decreased on average by 2 daily on the 2 heaviest menstrual flow days.100,112

Other Uses

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease† among patients who received an NSAIA for 2 years or longer.137,138 Similar findings have been reported from some other, but not all, observational studies.137,138,139,140,141,142

Administration

The potential benefits and risks of meclofenamate sodium therapy as well as alternative therapies should be considered prior to initiating meclofenamate sodium therapy.146

Meclofenamate sodium is administered orally.

Adverse GI effects may be minimized by administering the drug with meals, milk, or an aluminum and magnesium hydroxides antacid.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.146 Dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.

Dosage of meclofenamate sodium is expressed in terms of meclofenamic acid.

Inflammatory Diseases

Rheumatoid Arthritis and Osteoarthritis

For the symptomatic treatment of rheumatoid arthritis or osteoarthritis, the usual initial adult dosage of meclofenamic acid is 200-300 mg daily in 3 or 4 equally divided doses. Since adverse effects occur more commonly in geriatric patients, these patients should be given a lower initial dosage. Subsequent dosage should be adjusted according to the patient's response and tolerance but should not exceed 400 mg daily. Symptomatic improvement may occur after a few days of meclofenamate sodium therapy, but 2-3 weeks of treatment may be needed to obtain optimum effects. When a satisfactory response has been achieved, dosage should be reduced to the lowest possible effective level. If intolerable adverse effects occur, dosage may need to be reduced; therapy should be discontinued if the adverse effects are severe.

Pain

For the relief of mild to moderate pain, the usual adult dosage of meclofenamic acid is 50 mg every 4-6 hours.100,101,103,104,105,106 In some patients, a meclofenamic acid dosage of 100 mg every 4-6 hours may be required for optimal relief,100,101,102,103,104,105,106 but dosage should not exceed 400 mg daily.100,101

Dysmenorrhea and Menorrhagia

For the relief of primary dysmenorrhea or idiopathic menorrhagia, the usual adult dosage of meclofenamic acid is 100 mg 3 times daily.100,107,112 Therapy usually is initiated at the onset of menses and continued for up to 6 days thereafter or until the cessation of menses.100,112

Cardiovascular Effects

Peripheral edema and palpitations have been reported in patients receiving meclofenamate sodium.

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.147,154,500 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.150,151,152,154,500,501,502,503,506 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.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.146,502,508

GI Effects

Adverse reactions to meclofenamate sodium mainly involve the GI tract; severe reactions may require discontinuing the drug. The most frequent adverse effect is diarrhea which may be severe. Diarrhea is usually a dose-related effect, generally subsides when dosage is reduced, and usually resolves after discontinuance of the drug. In studies of up to 4 years' duration, about 33% of patients treated with meclofenamate sodium had at least one episode of diarrhea during therapy. During administration of meclofenamate sodium for up to 6 months in controlled studies, 10-33% of treated patients had diarrhea, 11% had nausea with or without vomiting, 3-9% had abdominal pain, and 10% had other adverse GI effects; in about 4% of treated patients, diarrhea was severe enough to require discontinuance of the drug. Patients with osteoarthritis may have a lower incidence of meclofenamate sodium-induced diarrhea than do those with rheumatoid arthritis.

Other reported adverse GI effects include pyrosis and flatulence and less frequently, anorexia, constipation, stomatitis, peptic ulcer and GI bleeding (including one fatality), gastric ulcer, eructation, GI bleeding and/or perforation (with or without obvious ulcer formation), colitis, spasm, and tenesmus. The manufacturers state that most patients who developed peptic ulcer while receiving meclofenamate sodium had a history of ulcer disease or were also receiving other anti-inflammatory drugs including corticosteroids. Although a causal relationship has not been directly determined, paralytic ileus has been reported during meclofenamate sodium therapy, and one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.

In a dosage of 300 mg daily, meclofenamate sodium has been reported to produce a similar incidence of adverse GI effects as 150 mg of indomethacin daily, but a greater incidence of adverse GI effects (mainly diarrhea) than 3.6 g of aspirin daily. The amount of GI bleeding as determined by fecal blood loss has been reported to be less with 300 or 400 mg of meclofenamate sodium daily than with 3.6 g of aspirin daily.

Adverse GI effects may be minimized by administering meclofenamate sodium with meals, milk, or an aluminum and magnesium hydroxides antacid. Close supervision of meclofenamate sodium therapy is necessary, particularly in patients with a history of upper GI disease.

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.108,109,117,146 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.146 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.108,109,146 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.108,109 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.146

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.108,109 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.108,109 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.146 However, short-term therapy is not without risk.146 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.108,109 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.108,109

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.134,136 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 use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status.134,136,143 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.120,134,136 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.100

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.111,120,134,135 (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.111,120,134 In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest.134 In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.134 Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers.120,134 Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs.120 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.144,145 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.144,145

Nervous System Effects

Adverse nervous system effects occasionally occur in patients receiving meclofenamate sodium. The most frequent adverse nervous system effects of meclofenamate sodium include dizziness and headache, which occur in 3-9% of patients. Vertigo, lack of concentration, and confusion also occur in some patients. Malaise, fatigue, drowsiness, paresthesia, asthenia, insomnia, and depression have also been reported, although a causal relationship to meclofenamate sodium has not been established.

Ocular and Otic Effects

Patients receiving meclofenamate sodium have experienced tinnitus. Blurred vision, decreased visual acuity, temporary loss of vision, retinal changes (including fibrosis), reversible loss of color vision, macular and perimacular edema, conjunctivitis, and iritis have occurred rarely in patients receiving meclofenamate sodium, but these effects have not been directly attributed to the drug. Ophthalmologic examinations of individuals prior to and after long-term therapy with meclofenamate sodium have shown no evidence of drug-induced changes. Because other NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during meclofenamate sodium therapy should have an ophthalmologic examination.

Hematologic Effects

Decreased hemoglobin concentration and hematocrit have occurred in patients receiving meclofenamate sodium; however, discontinuance of therapy was rarely required. There was no evidence of increased chronic blood loss, bone-marrow suppression, or hemolysis to account for the decreased hemoglobin concentration and hematocrit in these patients. If signs or symptoms of anemia appear in patients receiving prolonged therapy with the drug, hemoglobin concentration and hematocrit should be determined.

Decreased leukocyte counts have occurred rarely with meclofenamate sodium therapy and usually returned to pretreatment levels while the patient continued receiving the drug. Thrombocytopenic purpura, neutropenia, agranulocytosis, hemolytic anemia, and eosinophilia also have occurred rarely. Further clinical evaluations are necessary if leukopenia, granulocytopenia, or thrombocytopenia persists; discontinuance of meclofenamate sodium therapy may be necessary in some patients. Leukocytosis has been reported in at least one patient receiving meclofenamate sodium.

Meclofenamate sodium may transiently inhibit platelet aggregation but does not appear to affect bleeding time.

Renal Effects

Laboratory test abnormalities including elevations in BUN and serum creatinine concentrations have occurred occasionally in patients receiving meclofenamate sodium. Renal failure has been reported rarely. Nocturia has also occurred rarely, but a causal relationship to meclofenamate sodium has not been established. Hematuria and passage of an ureteral stone have been reported rarely in patients receiving meclofenamate sodium.

Long-term administration of NSAIAs has resulted in renal papillary necrosis and other renal injury.146

Hepatic Effects

Abnormal liver function test results, including increases in serum alkaline phosphatase and aminotransferase (transaminase) concentrations, have occurred in about 4% of patients receiving meclofenamate sodium. Cholestatic jaundice and elevations in serum bilirubin concentration also have occurred during therapy with the drug. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) have been reported in patients receiving NSAIAs.

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. Meclofenamate sodium should be discontinued if signs or symptoms of a severe hepatic reaction occur. (See Cautions: Precautions and Contraindications.)

Dermatologic Effects

Rash reportedly occurs in 3-9% of patients during meclofenamate sodium therapy; urticaria and pruritus occur less frequently. Erythema multiforme, Stevens-Johnson syndrome, and exfoliative dermatitis have occurred rarely. Erythema nodosum and alopecia have also been reported, but these effects have not been directly attributed to the drug.

Other Adverse Effects

Dyspnea, hot flushes, and perspiration have occurred rarely in patients receiving meclofenamate sodium, but these effects have not been directly attributed to the drug. Thrombophlebitis was reported in one patient with a history of the condition.

Lupus erythematosus-like and serum sickness-like symptoms have been reported in patients receiving meclofenamate sodium. Although a causal relationship to the drug has not been established, taste disturbances and myalgia have occurred rarely.

Precautions and Contraindications

Patients should be advised that meclofenamate sodium, 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.108,109,146,500,508 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.108,109 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.108,109

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.146

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.146,150,151,152,154,500,502,508 (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.146,500,508 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 possible development of cardiovascular events throughout therapy.146,500,508 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.146,500,508 Meclofenamate sodium 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 meclofenamate sodium 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.146,147,502,508 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.146 Because of the potential for increased adverse effects, patients receiving meclofenamate should be advised not to take aspirin.146

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.146 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.146,508,509 NSAIAs should be used with caution in patients with hypertension.146 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.146

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that meclofenamate sodium 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 meclofenamate sodium 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 left 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 meclofenamate sodium, particularly in patients receiving chronic therapy with the drug.108,109 (See Cautions: GI Effects.) Meclofenamate sodium should be used with caution in patients with a history of upper GI disease.118,119,123,134,135,136 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.146

Meclofenamate should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration, and such patients should receive an appropriate ulcer preventive regimen.118,119,123,134,135,136 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.118,119,123,134,135,136 To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed.146 For patients who are at high risk, alternative therapy other than an NSAIA should be considered.146

Patients receiving meclofenamate sodium should be evaluated periodically to ensure that the drug is still necessary and well tolerated. If abnormal blood chemistry values are obtained during therapy with the drug, the manufacturers recommend that follow-up studies be conducted.

Liver function should be monitored periodically during long-term meclofenamate therapy. 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 meclofenamate sodium should be evaluated for evidence of the development of a more severe hepatic reaction. Severe reactions, including jaundice, have occurred during therapy with meclofenamate sodium, and fatal hepatitis, liver necrosis, and hepatic failure (sometimes fatal) have occurred with other NSAIAs. Although such reactions are rare, meclofenamate sodium 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 meclofenamate sodium are at risk of developing adverse renal effects.100 Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.146 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.146 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.146,149 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.146 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.146 Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.

It is not known whether accumulation of meclofenamic acid or its metabolites occurs in patients with renal or hepatic impairment.100 Meclofenamate sodium should be used with caution and close monitoring in patients with substantial renal impairment, since the drug is eliminated principally by the kidneys. To avoid excessive accumulation of the drug, decreased dosages of meclofenamate sodium should be considered in these patients.

Patients should be warned that meclofenamate sodium may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Patients should be advised to consider discontinuing the drug and to contact their physician if severe nausea, vomiting, diarrhea, or abdominal pain occurs during meclofenamate sodium therapy.

Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during meclofenamate sodium therapy should have an ophthalmologic examination.

Each 100-mg meclofenamate sodium capsule contains 0.34 mEq of sodium; this should be considered in patients whose sodium intake must be restricted.

If signs or symptoms of anemia appear in patients receiving prolonged therapy with meclofenamate sodium, hemoglobin concentration and hematocrit should be determined.

Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration, and the drugs should be used concomitantly with caution. If corticosteroid dosage is decreased during meclofenamate sodium 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.

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.

Meclofenamate sodium should be used for primary dysmenorrhea or idiopathic menorrhagia only when the potential benefits justify the possible risks.100 In addition, the drug should be used only for heavy menstrual flow that is idiopathic in nature (i.e., no underlying pathophysiologic cause can be identified).100,112 Meclofenamate sodium should not be used for the management of spotting or bleeding that occurs between cycles.100 Women receiving the drug for menorrhagia should be advised to consult their physician if spotting or bleeding occurs between cycles or if no improvement in, or worsening of, their menstrual flow occurs;100 such manifestations should be evaluated fully since they may be signs of the development of a more serious condition that is not appropriately treated with meclofenamate sodium.100

Anaphylactoid reactions have been reported in patients receiving NSAIAs.146 Patients receiving meclofenamate sodium 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.146

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.146 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.146 Meclofenamate sodium should be discontinued at the first appearance of rash or any other sign of hypersensitivity.146

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.1201 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.1201 Symptoms may resemble those of an acute viral infection.1201 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.1201 If such signs or symptoms develop, meclofenamate sodium should be discontinued and the patient evaluated immediately.1201

The manufacturers state that meclofenamate sodium is contraindicated in patients with known hypersensitivity to the drug.100 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.146 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.146 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.146 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 meclofenamate sodium in children younger than 14 years of age have not been established.

Geriatric Precautions

Meclofenamate sodium should be used with caution in geriatric individuals since increasing age may be associated with increased risk of adverse effects; particular attention should be paid to the meclofenamate sodium dosage (i.e., initiate therapy with a lower than usual dosage).100 Geriatric individuals appear to tolerate GI ulceration and bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.100

Carcinogenicity

No evidence of carcinogenicity was observed when rats were given meclofenamate sodium for 18 months.

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.1200,1201 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.1200,1201 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.1200,1201 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.1200,1201

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.1200,1201 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.1200,1201 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.1200,1201 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.1200,1201 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.1200,1201 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.1201 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.1201 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.1201

Animal reproduction studies in rats and rabbits have not demonstrated evidence of developmental abnormalities with meclofenamate.1201 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 meclofenamate, were associated with increased pre- and post-implantation losses.1201 Prostaglandins also have an important role in fetal kidney development.1201 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.1201

The effects of meclofenamate sodium 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, and decreased pup survival.1201

Fertility

Use of NSAIAs may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.1203 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.1203 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.1203

Lactation

Meclofenamic acid is distributed in trace amounts into human milk.100 In suckling rodents, the drug interferes with normal development before weaning. Because of its effect in rodents and possible adverse effects secondary to inhibition of prostaglandin synthesis in neonates, the manufacturers recommend that meclofenamate sodium not be used in nursing women and a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Protein-bound Drugs

Because meclofenamate is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Patients receiving meclofenamate sodium with any of these drugs should be observed for adverse effects.

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

There is some evidence that concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.146,153

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic.146 Concomitant use of NSAIAs and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.146

Meclofenamate sodium enhances the hypoprothrombinemic effect of warfarin, especially during the first 1-2 weeks of meclofenamate sodium therapy. If the drugs are used concurrently, prothrombin time should be monitored carefully and warfarin dosage should be adjusted accordingly, and patients should be observed for adverse effects. In addition, the ulcerogenic potential of meclofenamate sodium and the effect of the drug on platelet function may further contribute to the hazard of concomitant therapy with any anticoagulant or thrombolytic agent (e.g., streptokinase).

Nonsteroidal Anti-inflammatory Agents

Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.137 Because of the potential for increased adverse effects, patients receiving meclofenamate should be advised not to take aspirin.146 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.147,502,508

Administration of aspirin with meclofenamate sodium may decrease plasma concentrations of meclofenamic acid, possibly by competing for protein-binding sites; the urinary excretion of meclofenamate sodium is unaffected by aspirin. Serum salicylate concentrations are not affected by concurrent administration of the drugs. Concomitant administration of aspirin and meclofenamate sodium results in a greater fecal blood loss than that from either drug alone. The concomitant use of salicylates and meclofenamate sodium is not recommended.

Diuretics

NSAIAs can reduce the natriuretic effects of furosemide or thiazide diuretics.146 This effect may be related to inhibition of renal prostaglandin synthesis.146 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for signs of renal failure and for efficacy of the diuretic.146

Lithium

NSAIAs appear to decrease renal clearance of lithium.146 The mechanism involved in the reduction of lithium clearance by NSAIAs is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium.146 If meclofenamate sodium and lithium are used concomitantly, the patient should be observed for signs and symptoms of lithium toxicity.146

Methotrexate

Because of the possibility of enhanced toxicity of methotrexate, caution is advised if methotrexate and an NSAIA are administered concomitantly.146 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.)

Pemetrexed

Concomitant use of NSAIAs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.1203 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.1203 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.1203 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant NSAIA and pemetrexed therapy.1203

Other Drugs

Concurrent administration of propoxyphene and meclofenamate sodium reportedly does not affect the bioavailability of meclofenamate sodium.

Meclofenamate sodium should be used cautiously, if at all, with other drugs that might potentiate the adverse GI effects.

Acute Toxicity

Limited information is available on the acute toxicity of meclofenamate sodium.

Manifestations

Following acute, massive overdosage, CNS stimulation, manifested as irrational behavior, marked agitation, and generalized seizures, may occur. This initial phase may be followed by renal toxicity, including decreased urine output, increased serum creatinine concentration, and abnormal urinary cellular elements, and may be accompanied by oliguria or anuria and azotemia. In a 24-year-old male who ingested 6-7 g of meclofenamate, anuria persisted for about 1 week before diuresis and recovery occurred.

Treatment

In acute overdosage, the stomach should be emptied immediately by inducing emesis or by gastric lavage, followed by administration of activated charcoal. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and symptomatic treatment should be initiated. Patients should be monitored carefully to preserve vital functions and maintain fluid and electrolyte balance. Seizures should be controlled with an appropriate anticonvulsant regimen (e.g., IV diazepam). Hemodialysis, peritoneal dialysis, and hemoperfusion are probably of no value in enhancing elimination of the drug, since meclofenamate sodium is highly bound to plasma proteins; however, dialysis may be required to correct serious azotemia or electrolyte abnormalities.

Pharmacology

Meclofenamate sodium 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. Like other NSAIAs, meclofenamate sodium 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.127,128,129,130,131,132 Meclofenamate, like other prototypical NSAIAs, inhibits COX-1 and COX-2.127,128,129,130,131,132 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.127,128,129,130,131,132 Unlike most other NSAIAs, the fenamates, including meclofenamate sodium, also 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 meclofenamate sodium 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.127,128,129,130,131,132

The hydroxymethyl metabolite of meclofenamic acid appears to have considerable anti-inflammatory activity. Meclofenamate sodium does not possess glucocorticoid or adrenocorticoid-stimulating properties.

The antipyretic effect of meclofenamate sodium has been demonstrated in animals. 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

Meclofenamate sodium-induced inhibition of prostaglandin synthesis may result in decreased uterine tone and contractility.107,112,113 Prostaglandins E₂ and F_2α increase the amplitude and frequency of uterine contractions in pregnant women; current evidence suggests that primary dysmenorrhea also is mediated by these prostaglandins.112,113,115,116 Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined.133 In some patients, meclofenamate sodium has relieved symptoms associated with primary dysmenorrhea and menorrhagia.100,107,112 Therapy with meclofenamate sodium has been effective in relieving menstrual pain107,112 and in reducing intrauterine pressure and uterine activity107 in women with primary dysmenorrhea and has reduced blood loss100,112 in women with menorrhagia, probably by inhibiting the synthesis and/or actions of these prostaglandins.107,112,113

Meclofenamate sodium has been reported to adversely affect renal function. (See Cautions: Renal Effects.) Although the exact mechanisms of adverse renal effects have not been determined, they may be related to inhibition of renal prostaglandin synthesis. The drug does not appear to have uricosuric activity.

GI Effects

Meclofenamate sodium 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-1.127,128,129,130,131,132,134 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.129,134

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.131 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.131

Hematologic Effects

Meclofenamate sodium can transiently inhibit platelet aggregation but does not appear to affect bleeding time. Similar to aspirin and other prototypical NSAIAs, the effects of meclofenamate on platelets appear to be associated with the inhibition of the synthesis of prostaglandins produced by COX-1.131 In one multiple-dose study in healthy individuals, the drug had little or no effect on collagen-induced platelet aggregation, platelet count, or bleeding time.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, the drug was administered as the sodium salt; dosage is expressed in terms of meclofenamic acid.

Absorption

Meclofenamic acid appears to be rapidly and completely absorbed from the GI tract. Food decreases both the rate27,100 and extent100 of absorption of the drug, resulting in delayed and decreased peak plasma concentrations of meclofenamic acid27,100 and decreased bioavailability.100 Following oral administration of meclofenamate sodium 30 minutes after ingestion of food, bioavailability of the drug decreased on average by 26%, peak plasma concentrations decreased on average fourfold, and time to reach peak plasma concentration was delayed by 3 hours.100 Concomitant administration of an aluminum and magnesium hydroxides antacid does not appear to alter the absorption of meclofenamic acid.

Following oral administration of a single 100-mg dose of meclofenamic acid to healthy fasting adults in one study, peak plasma drug concentrations of approximately 5-9 mcg/mL were reached in 30-60 minutes.2 Following oral administration of 100 mg of meclofenamic acid 3 times daily for up to 14 days in healthy adults, peak plasma drug (unchanged) concentrations of about 2-5 mcg/mL were reached 0.5-2 hours after dosing.2,100,114 Peak plasma concentrations of the 3-hydroxymethyl metabolite averaging 1 mcg/mL were achieved within 2.4 hours (range: 0.5-4 hours) in these adults during multiple dosing, and total peak plasma concentrations of this metabolite (the metabolite plus its conjugates) averaging 4.7 mcg/mL were achieved.100,114 Appreciable accumulation of meclofenamic acid does not appear to occur during repeated dosing in healthy adults;100,114 however, it is not known whether accumulation of the drug occurs in patients with renal and/or hepatic impairment.100 Accumulation of the 3-hydroxymethyl and the 3-carboxylic acid metabolites does appear to occur in healthy adults during repeated dosing;100,114 however, only the 3-hydroxymethyl metabolite is active.2,100,114 Although the clinical importance of accumulation of the 3-hydroxymethyl metabolite remains to be elucidated114 and the manufacturer suggests that it may not be important,100 estimates from pharmacokinetic data and in vitro potency studies suggest that a substantial proportion of the activity of the drug may result from this metabolite.114 Plasma drug concentrations required for anti-inflammatory effect have not been determined.

Distribution

Distribution of meclofenamic acid into human body tissues and fluids has not been fully elucidated. The apparent volume of distribution of the drug in healthy adults is approximately 23.3 L (range: 9.1-43.2 L) following oral administration.100 In monkeys, concentrations of radioactivity after administration of meclofenamic acid H 3 are highest in the plasma, liver, and kidneys, with lower concentrations in the heart, spleen, fat, skeletal muscle, and brain. At drug concentrations of 1-130 mcg/mL, approximately 99.8% of meclofenamic acid is protein bound, principally to albumin.2,100,114 Meclofenamic acid rapidly crosses the placenta in monkeys. Trace amounts of the drug are distributed into human milk.

Elimination

The apparent plasma elimination half-life of meclofenamic acid in healthy adults has been reported to range from 40 minutes to 5.3 hours following a single dose2,100,114 and approximately 50 minutes to 3.3 hours following multiple doses of 100 mg 3 times daily.2,27,100,114

Meclofenamic acid is extensively metabolized to 2 major and at least 6 minor metabolites.2,27,100,114 The drug is metabolized principally by oxidation of the ring methyl group to a pharmacologically active 3-hydroxymethyl metabolite, which may be further oxidized to an inactive carboxylic acid metabolite.2,27,100,114 To a lesser extent, ring hydroxylation and monodehalogenation of meclofenamic acid also occur. Glucuronic acid conjugates of these metabolites are also formed. The 3-hydroxymethyl metabolite is the only metabolite of meclofenamic acid that has been shown to inhibit cyclooxygenase in vitro, exhibiting about 20% of pharmacologic activity of the parent drug.2,100,114 In healthy adults, the apparent plasma elimination half-life of the 3-hydroxymethyl metabolite averages about 12-15 hours or longer during repeated dosing of 100 mg 3 times daily,100,114 but that of total 3-hydroxymethyl metabolites (the metabolite plus its conjugates) varies greatly, ranging from 4-31 hours.114 Total plasma concentration of this metabolite greatly exceeds the unconjugated concentration, suggesting that the drug undergoes enterohepatic circulation.114

Following oral administration in healthy adults, about 70% of a dose of meclofenamic acid is excreted in urine, principally as glucuronide conjugates of the metabolites.2,27,100,114 About 20-30% of the dose is excreted in feces, probably via biliary elimination.2,27,100 About 8-35% of an oral dose is excreted in urine almost exclusively as conjugates of meclofenamic acid and its 3-hydroxymethyl metabolite (only trace amounts are unconjugated),2,27,100,114 while the remaining 35-62% of an oral dose is excreted as the other metabolites, for a total urinary excretion of about 70% of a dose.2,100

Chemistry and Stability

Chemistry

Meclofenamic acid, an anthranilic acid derivative (fenamate), is a prototypical nonsteroidal anti-inflammatory agent (NSAIA). The drug is structurally and pharmacologically related to mefenamic acid. Meclofenamic acid is commercially available as the sodium monohydrate salt; however, potency of the commercially available capsules is expressed in terms of meclofenamic acid. Meclofenamate sodium monohydrate occurs as a white to creamy white, odorless to almost odorless, crystalline powder and is freely soluble in water and soluble in alcohol. The apparent pK_a of the drug is 4.0. Each 100-mg capsule of meclofenamate sodium contains 0.34 mEq of sodium.

Stability

Meclofenamate capsules should be stored in tight, light-resistant containers at a controlled room temperature of 15-30°C.

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.

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