MECLOFENAMATE: 11 Adverse Event Reports & Safety Profile

DESCRIPTION Meclofenamate sodium is N-(2,6-dichloro-m-tolyl) anthranilic acid, sodium salt, monohydrate. It is an anti-inflammatory drug for oral administration. Meclofenamate sodium capsules, USP contain 50 mg or 100 mg meclofenamic acid as the sodium salt and the following inactive ingredients: colloidal silicon dioxide, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 3, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium lauryl sulfate and titanium dioxide. In addition, the imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. The structural formula of meclofenamate sodium is: Molecular Formula: C 14 H 10 Cl 2 NNaO 2

• H 2 O It is a white to creamy white, odorless to almost odorless, crystalline powder with melting point 287° to 291°C, molecular weight 336.15, and it is freely soluble in water.

Meclofenamate Sodium Structural

Formula

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of meclofenamate sodium capsules and other treatment options before deciding to use meclofenamate sodium capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Meclofenamate sodium capsules are indicated:

• For reduction of fever in adults
• For relief of mild to moderate pain in adults
• For relief of signs and symptoms of juvenile arthritis.
• For relief of the signs and symptoms of rheumatoid arthritis
• For relief of the signs and symptoms of osteoarthritis.
• For treatment of primary dysmenorrhea.
• For acute or long-term use in the relief of signs and symptoms of the following: 1. Ankylosing spondylitis 2. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis) 3. Acute gouty arthritis Meclofenamate sodium capsules are also indicated for the treatment of idiopathic heavy menstrual blood loss (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). As with all nonsteroidal anti-inflammatory drugs, selection of meclofenamate sodium capsules require a careful assessment of the benefit/risk ratio (see WARNINGS , PRECAUTIONS and ADVERSE REACTIONS ). Meclofenamate sodium capsules are not recommended in children because adequate studies to demonstrate safety and efficacy have not been carried out.

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of meclofenamate sodium capsules and other treatment options before deciding to use meclofenamate sodium capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with meclofenamate sodium capsules, the dose and frequency should be adjusted to suit an individual patient's needs.

Usual Dosage For

Mild to Moderate Pain The recommended dose is 50 mg every 4 to 6 hours. Doses of 100 mg may be needed in some patients for optimal pain relief (see CLINICAL PHARMACOLOGY ). However, the daily dose should not exceed 400 mg (see ADVERSE REACTIONS ). For excessive menstrual blood loss and primary dysmenorrheal The recommended dose of meclofenamate sodium is 100 mg 3 times a day, for up to 6 days, starting at the onset of menstrual flow. For rheumatoid arthritis and osteoarthritis (including acute exacerbations of chronic disease) The dosage is 200 mg to 400 mg per day, administered in three or four equal doses. Therapy should be initiated at the lower dosage, then increased as necessary to improve clinical response. The dosage should be individually adjusted for each patient, depending on the severity of the symptoms and the clinical response. The daily dosage should not exceed 400 mg per day. The smallest dosage of meclofenamate sodium that yields clinical control should be employed. Although improvement may be seen in some patients in a few days, 2 to 3 weeks of treatment may be required to obtain the optimum therapeutic benefit. After a satisfactory response has been achieved, the dosage should be adjusted as required. A lower dosage may suffice for long-term administration. If gastrointestinal complaints occur (see WARNINGS and PRECAUTIONS ), meclofenamate sodium may be administered with meals or with milk (see CLINICAL PHARMACOLOGY for a description of food effects). If intolerance occurs, the dosage may need to be reduced. Therapy should be terminated if any severe adverse reactions occur.

CONTRAINDICATIONS Meclofenamate sodium capsules are contraindicated in patients with known hypersensitivity to meclofenamate sodium. Meclofenamate sodium capsules should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma ). Meclofenamate sodium capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

ADVERSE REACTIONS 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.

Gastrointestinal

The most frequently reported adverse reactions associated with meclofenamate sodium involve the gastrointestinal system. In controlled studies of up to 6 months duration, these disturbances occurred in the following decreasing order of frequency with the approximate incidences in parentheses: diarrhea (10% to 33%), nausea with or without vomiting (11%), other gastrointestinal disorders (10%), and abdominal pain * . In long-term uncontrolled studies of up to 4 years duration, one third of the patients had at least one episode of diarrhea some time during meclofenamate sodium therapy. In approximately 4% of the patients in controlled studies, diarrhea was severe enough to require discontinuation of meclofenamate sodium. The occurrence of diarrhea is dose related, generally subsides with dose reduction, and clears with termination of therapy. The incidence of diarrhea in patients with osteoarthritis is generally lower than that reported in patients with rheumatoid arthritis. Other reactions less frequently reported were pyrosis * , flatulence * , anorexia, constipation, stomatitis, and peptic ulcer. The majority of the patients with peptic ulcer had either a history of ulcer disease or were receiving concomitant anti-inflammatory drugs, including corticosteroids which are known to produce peptic ulceration. Cardiovascular: edema Dermatologic: rash * , urticaria, pruritus Central Nervous System: headache * , dizziness * Special Senses: tinnitus * Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.

Incidence Less Than

1%—Probably Causally Related The following adverse reactions were reported less frequently than 1% during controlled clinical trials and through voluntary reports since marketing. The probability of a causal relationship exists between the drug and these adverse reactions. Gastrointestinal: bleeding and/or perforation with or without obvious ulcer formation, colitis, cholestatic jaundice Renal: renal failure Hematologic: neutropenia, thrombocytopenic purpura, leukopenia, agranulocytosis, hemolytic anemia, eosinophilia, decrease in hemoglobin and/or hematocrit Dermatologic: erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE) Hepatic: alteration of liver function tests Allergic: lupus and serum sickness-like symptoms 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

WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meclofenamate sodium, increases the risk of serious gastrointestinal (GI) events (see WARNINGS ).

Status Post Coronary Artery Bypass

Graft (CABG)

Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up. Avoid the use of meclofenamate sodium capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meclofenamate sodium capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including meclofenamate sodium, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including meclofenamate sodium, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Heart

Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meclofenamate sodium may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] (see Drug Interactions ). Avoid the use of meclofenamate sodium capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meclofenamate sodium capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Gastrointestinal Effects

Risk of Ulceration, Bleeding, and Perforation NSAIDs, including meclofenamate sodium, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

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.

Advanced Renal

Disease No information is available from controlled clinical studies regarding the use of meclofenamate sodium in patients with advanced renal disease. Therefore, treatment with meclofenamate sodium is not recommended in these patients with advanced renal disease. If meclofenamate sodium therapy must be initiated, close monitoring of the patient's renal function is advisable.

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 Premature

Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including meclofenamate sodium capsules, in pregnant women at about 30 weeks gestation and later. NSAIDs including meclofenamate sodium capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs, including meclofenamate sodium capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meclofenamate sodium capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meclofenamate sodium capsules treatment extends beyond 48 hours. Discontinue meclofenamate sodium capsules if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS: Pregnancy ).

PRECAUTIONS 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 ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

When meclofenamate sodium in administered with aspirin, its protein binding is reduced, although the clearance of free meclofenamate sodium is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meclofenamate sodium capsules and aspirin is not generally recommended because of the potential of increased adverse effects.

Furosemide

Clinical studies, as well as post-marketing observations, have shown that meclofenamate sodium can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see PRECAUTIONS: Renal Effects ), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Carcinogenesis An

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

Pregnancy Risk Summary

Use of NSAIDs, including meclofenamate sodium capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of meclofenamate sodium capsules use between about 20 and 30 weeks of gestation, and avoid meclofenamate sodium capsules use at about 30 weeks of gestation and later in pregnancy (see WARNINGS: Fetal Toxicity ).

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meclofenamate sodium capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Animal reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meclofenamate, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meclofenamate sodium capsules, can cause premature closure of the fetal ductus arteriosus (see WARNINGS: Fetal Toxicity ).

Oligohydramnios/Neonatal

Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meclofenamate sodium capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meclofenamate sodium capsules and follow up according to clinical practice (see WARNINGS: Fetal Toxicity ).

Data Human Data Premature

Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. 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).

Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

When meclofenamate sodium in administered with aspirin, its protein binding is reduced, although the clearance of free meclofenamate sodium is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meclofenamate sodium capsules and aspirin is not generally recommended because of the potential of increased adverse effects.

Furosemide

Clinical studies, as well as post-marketing observations, have shown that meclofenamate sodium can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see PRECAUTIONS: Renal Effects ), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.