Pharmacodynamics

Meclofenamate sodium is a nonsteroidal agent which has demonstrated anti-inflammatory, analgesic, and antipyretic activity in laboratory animals. The mode of action, like that of other nonsteroidal anti-inflammatory agents, is not known. Therapeutic action does not result from pituitary-adrenal stimulation. In animal studies, meclofenamate sodium was found to inhibit prostaglandin synthesis and to compete for binding at the prostaglandin receptor site. In vitro, meclofenamate sodium was found to be an inhibitor of human leukocyte 5-lipoxygenase activity. These properties may be responsible for the anti-inflammatory action of meclofenamate sodium. There is no evidence that meclofenamate sodium alters the course of the underlying disease.

In several human isotope studies, meclofenamate sodium, at a dosage of 300 mg/day, produced a fecal blood loss of 1 to 2 mL per day, and 2 to 3 mL per day at 400 mg/day. Aspirin, at a dosage of 3.6 g/day, caused a fecal blood loss of 6 mL per day.

In a multiple-dose, 1-week study in normal human volunteers, meclofenamate sodium had little or no effect on collagen-induced platelet aggregation, platelet count, or bleeding time. In comparison, aspirin suppressed collagen-induced platelet aggregation and increased bleeding time. The concomitant administration of antacids (aluminum and magnesium hydroxides) does not interfere with absorption of meclofenamate sodium.

Pharmacokinetics

Meclofenamate sodium is rapidly absorbed in man following single and multiple oral doses with peak plasma concentrations occurring in 0.5 to 2 hours. Based on a comparison to a suspension of meclofenamic acid, meclofenamate sodium is completely bioavailable.

The plasma concentrations of meclofenamic acid decline monoexponentially following oral administration. In a study in ten healthy subjects following a single oral dose the apparent elimination half-life ranged from 0.8 to 5.3 hours. After the administration of meclofenamate sodium for 14 days every 8 hours, the apparent elimination half-life ranged from 0.8 to 2.1 hours with no evidence of accumulation of meclofenamic acid in plasma (see Table).

Meclofenamic acid is extensively metabolized to an active metabolite (Metabolite I; 3-hydroxymethyl metabolite of meclofenamic acid) and at least six other less well characterized minor metabolites. Only this Metabolite I has been shown in vitro to inhibit cyclooxygenase activity with approximately one fifth the activity of meclofenamate sodium. Metabolite I (3-hydroxymethyl metabolite of meclofenamic acid) with a mean half-life of approximately 15 hours did accumulate following multiple dosing. After the administration of 100 mg meclofenamate sodium for 14 days every 8 hours, Metabolite I reached a peak plasma concentration of only 1 mcg/mL. By contrast, the peak concentration was 4.8 mcg/mL for the parent compound on both days 1 and 14. Therefore, the accumulation of Metabolite I is probably not clinically significant.

Approximately 70% of the administered dose is excreted by the kidneys with 8% to 35% excreted as predominantly conjugated species of meclofenamic acid and Metabolite I (see Table). Other metabolites, whose excretion rates are unknown, account for the remaining 35% to 62% of the dose excreted in the urine. The remainder of the administered dose (approximately 30%) is eliminated in the feces (apparently through biliary excretion). There is insufficient experience to know if meclofenamate sodium or its metabolites accumulate in patients with compromised renal or hepatic function. Therefore, meclofenamate sodium should be used with caution in these patients (see PRECAUTIONS). Trace amounts of meclofenamate sodium are excreted in human breast milk.

Meclofenamic acid is greater than 99% bound to plasma proteins over a wide drug concentration range.

Unlike most NSAIDs, which when administered with food have a decrease in rate but not in extent of absorption, meclofenamic acid is decreased in both. It has been reported that following the administration of meclofenamate sodium capsules one-half hour after a meal, the average extent of bioavailability decreased by 26%, the average peak concentration (Cmax) decreased 4-fold and the time to Cmax was delayed by 3 hours.

Clinical Studies

Controlled clinical trials comparing meclofenamate sodium with aspirin demonstrated comparable efficacy in rheumatoid arthritis.

The meclofenamate sodium treated patients had fewer reactions involving the special senses, specifically tinnitus, but more gastrointestinal reactions, specifically diarrhea.

The incidence of patients who discontinued therapy due to adverse reactions was similar for both the meclofenamate sodium and aspirin-treated groups.

The improvement with meclofenamate sodium reported by patients and the reduction of the disease activity as evaluated by both physicians and patients with rheumatoid arthritis are associated with a significant reduction in number of tender joints, severity of tenderness, and duration of morning stiffness.

The improvement reported by patients and as evaluated by physicians in patients treated with meclofenamate sodium for osteoarthritis is associated with a significant reduction in night pain, pain on walking, degree of starting pain, and pain on passive motion. The function of knee joints also improved significantly.

Meclofenamate sodium has been used in combination with gold salts or corticosteroids in patients with rheumatoid arthritis. Studies have demonstrated that meclofenamate sodium contributes to the improvement of patients’ conditions while maintained on gold salts or corticosteroids. Data are inadequate to demonstrate that meclofenamate sodium in combination with salicylates produces greater improvement than that achieved with meclofenamate sodium alone.

In controlled clinical trials of patients with mild to moderate pain, meclofenamate sodium 50 mg provided significant pain relief. In these studies of episiotomy and dental pain, meclofenamate sodium 100 mg demonstrated additional benefit in some patients. The onset of analgesic effect was generally within one hour and the duration of action was 4 to 6 hours.

In controlled clinical trials of patients with dysmenorrhea, meclofenamate sodium 100 mg t.i.d. provided significant reduction in the symptoms associated with dysmenorrhea.

In randomized double-blind crossover trials of meclofenamate sodium 100 mg t.i.d. versus placebo in women with heavy menstrual blood loss (MBL), meclofenamate sodium treatment was usually associated with a reduction in menstrual flow.

The graph below is a scatter plot of menstrual flow from the average of two menstrual periods on meclofenamate sodium treatments (vertical axis) versus two menstrual periods on placebo (horizontal axis) for 55 women. Of note, although the amount of reduction in MBL was variable, some degree of reduction occurred in 90% of women in this study.

Scattergram of Menstrual Flow Average of Two Periods on Each Treatment of 55 Women from Three Clinical Trials

The points on the graph represent the mean MBL for each subject when treated for two periods with placebo and two periods with meclofenamate sodium. To ease in interpretation, the following examples may be helpful. Point A represents a woman who had MBL of 459 mL while on placebo, and 405 mL on meclofenamate sodium. Point B represents a woman who had MBL of 472 mL while on placebo, and 64 mL when treated with meclofenamate sodium.

In association with this reduction in menstrual blood loss, the duration of menses was decreased by one day; tampon/pad usage was decreased by an average of two per day on the 2 days of heaviest flow; and symptoms of dysmenorrhea were significantly reduced.

Cardiovascular Effects

Gastrointestinal Effects

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to meclofenamate sodium. Meclofenamate sodium should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Serious Skin Reactions

NSAIDs, including meclofenamate sodium, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant knows as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meclofenamate sodium capsules at the first appearance of skin rash or any other sign of hypersensitivity. Meclofenamate sodium capsules are contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS).

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meclofenamate sodium capsules. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meclofenamate sodium capsules and evaluate the patient immediately.

Fetal Toxicity

General

Meclofenamate sodium cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of meclofenamate sodium in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including meclofenamate sodium. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with meclofenamate sodium. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), meclofenamate sodium should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including meclofenamate sodium. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including meclofenamate sodium, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving meclofenamate sodium who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, meclofenamate sodium should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1.

Cardiovascular Thrombotic Events: Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS).

2.

Meclofenamate sodium, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).

3.

Serious Skin Reactions, including DRESS: Advise patients to stop taking meclofenamate sodium capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see WARNINGS).

4.

Heart Failure and Edema: Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS).

5.

Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

6.

Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).

7.

Fetal Toxicity: Inform pregnant women to avoid use of meclofenamate sodium capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meclofenamate sodium capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see WARNINGS: Fetal Toxicity, PRECAUTIONS: Pregnancy).

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meclofenamate sodium should be discontinued.

Drug Interactions

Carcinogenesis

An 18-month study in rats revealed no evidence of carcinogenicity.

Pregnancy

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of meclofenamate sodium on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human-milk and because of the potential for serious adverse reactions in nursing infants from meclofenamate sodium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 14 have not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

Incidence Greater Than 1%

The following adverse reactions were observed in clinical trials and included observations from more than 2,700 patients, 594 of whom were treated for one year and 248 for at least 2 years.

Incidence Less Than 1%—Causal Relationship Unknown

Other reactions have been reported but under conditions where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to alert physicians.

Cardiovascular: palpitations

Central Nervous System: malaise, fatigue, paresthesia, insomnia, depression

Special Senses: blurred vision, taste disturbances, decreased visual acuity, temporary loss of vision, reversible loss of color vision, retinal changes including macular fibrosis, macular and perimacular edema, conjunctivitis, iritis

Renal: nocturia

Gastrointestinal: paralytic ileus

Dermatologic: erythema nodosum, hair loss

Usual Dosage