WARNINGS
Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy
Serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
PRECAUTIONS
General
Patients receiving non-steroidal anti-inflammatory agents, such as meclofenamate sodium, should be evaluated periodically to insure that the drug is still necessary and well tolerated (see other PRECAUTIONS, WARNINGS, and ADVERSE REACTIONS).
Diarrhea, gastrointestinal irritation and abdominal pain may be associated with meclofenamate sodium therapy. Dosage reduction or temporarily stopping the drug have generally controlled these symptoms (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
Decreases in hemoglobin and/or hematocrit levels have occurred in approximately 1 of 6 patients, but rarely required discontinuation of meclofenamate sodium therapy. The clinical data revealed no evidence of increased chronic blood loss, bone marrow suppression, or hemolysis to account for the decreases in hemoglobin or hematocrit levels. Patients who are receiving long-term meclofenamate sodium therapy should have hemoglobin and hematocrit values determined if anemia is suspected on clinical grounds.
If a patient develops visual symptoms (see ADVERSE REACTIONS) during meclofenamate sodium therapy, the drug should be discontinued and the patient should have a complete ophthalmologic examination.
When meclofenamate sodium is used in combination with steroid therapy, any reduction in steroid dosage should be gradual to avoid the possible complications of sudden steroid withdrawal.
Elderly
Adverse effects are seen more commonly in the elderly; therefore, a lower starting dose and careful follow-up are advised.
Evaluation of Patients with Heavy Menstrual Blood Loss
Prior to prescribing meclofenamate sodium for heavy blood flow and primary dysmenorrhea, a thorough risk/benefit assessment should be made that takes into account the results described in the CLINICAL PHARMACOLOGY section. It is recommended that meclofenamate sodium treatment not be prescribed for heavy menstrual flow without establishing its idiopathic nature. Spotting or bleeding between cycles should be evaluated fully and not treated with meclofenamate sodium. Worsening of menstrual blood loss or excessive blood loss failing to respond to meclofenamate sodium should also be evaluated by an appropriate work-up and not treated with meclofenamate sodium.
Hepatic Reactions
As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in some patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (three times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 more severe hepatic reaction while on therapy with meclofenamate sodium. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with other non-steroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.; eosinophilia, rash), meclofenamate sodium should be discontinued.
Renal Effects
As with other non-steroidal anti-inflammatory drugs, long-term administration of meclofenamate sodium to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and 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 the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
Since meclofenamate sodium metabolites are eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be employed to avoid excessive drug accumulation.
Information for Patients
Patients should be advised that nausea, vomiting, diarrhea, and abdominal pain have been associated with the use of meclofenamate sodium. The patient should be made aware of a possible drug connection and accordingly should consider discontinuing the drug and contacting his or her physician if any of these conditions are severe.
Women who are taking meclofenamate sodium for heavy menstrual flow should be advised to consult their doctor if they have spotting or bleeding between cycles or worsening of their menstrual blood flow. These symptoms may be signs of the development of a more serious condition that is not appropriately treated with meclofenamate sodium.
Meclofenamate sodium may be taken with meals or milk to control gastrointestinal complaints. Concomitant administration of an antacid (specifically, aluminum and magnesium hydroxides) does not interfere with the absorption of the drug.
Meclofenamate sodium, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort, and rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.
NSAIDs (non-steroidal anti-inflammatory drugs) are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Laboratory Tests
Patients receiving long-term meclofenamate sodium therapy should have hemoglobin and hematocrit values determined if signs or symptoms of anemia occur.
Low white blood cell counts were rarely observed in clinical trials. These low counts were transient and usually returned to normal while the patient continued on meclofenamate sodium therapy. Persistent leukopenia, granulocytopenia, or thrombocytopenia warrant further clinical evaluation and may require discontinuation of the drug.
When abnormal blood chemistry values are obtained, follow-up studies are indicated.
Elevations of serum transaminase levels and of alkaline phosphatase levels occurred in approximately 4% of patients. An occasional patient had elevations of serum creatinine or BUN levels.
Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS: Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy).
Drug Interactions
1. Warfarin
Meclofenamate sodium enhances the effect of warfarin. Therefore, when meclofenamate sodium is given to a patient receiving warfarin, the dosage of warfarin should be reduced to prevent excessive prolongation of the prothrombin time.
2. Aspirin
Concurrent administration of aspirin may lower meclofenamate sodium plasma levels, possibly by competing for protein binding sites. The urinary excretion of meclofenamate sodium is unaffected by aspirin, indicating no change in meclofenamate sodium absorption. Meclofenamate sodium does not affect serum salicylate levels. Greater fecal blood loss results from concomitant administration of both drugs than from either drug alone.
3. Propoxyphene
The concurrent administration of propoxyphene hydrochloride does not affect the bioavailability of meclofenamate sodium.
4. Antacids
Concomitant administration of aluminum and magnesium hydroxides does not interfere with absorption of meclofenamate sodium.
Carcinogenesis
An 18 month study in rats revealed no evidence of carcinogenicity.
Pregnancy
Meclofenamate sodium, like aspirin and other non-steroidal anti-inflammatory drugs, causes fetotoxicity, minor skeletal malformations, e.g., supernumerary ribs, and delayed ossification in rodent reproduction trials, but no major teratogenicity. Similarly, it prolongs gestation and interferes with parturition and with normal development of young before weaning. Meclofenamate sodium is not recommended for use during pregnancy, particularly in the 1st and 3rd trimesters based on these animal findings. There are, however, no adequate and well controlled studies in pregnant women.
Nursing Mothers
Trace amounts of meclofenamic acid are excreted in human milk. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, meclofenamate sodium is not recommended for nursing women.
Pediatric Use
Safety and effectiveness in children below the age of 14 have not been established.
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