mefenamic acid (Rx)

>10%

Borderline elevations of one or more LFTs (<15%)

1-10%

Abdominal pain

Anorexia

Diarrhea

Nausea

Pyrosis

Gastritis

Flatulence

Constipation

Steatorrhea

Upper GI ulcers, gross bleeding/perforation (1% of patients treated for 3-6 mth and 2-4% of those treated for 1 yo)

<1%

Leukopenia

Eosinophilia

Thrombocytopenic purpura

Agranulocytosis

Pancytopenia

Bone marrow hypoplasia

Renal failure (including papillary necrosis & acute interstitial nephritis)

Acute interstitial nephritis has been associated with hematuria, proteinuria, & nephrotic syndrome

Contraindications

Hypersensitivity, ASA allergy, history of aspirin triad, GI tract ulcer/inflammation, CABG, renal dz, late pregnancy (may cause premature closure of ductus arteriosus)

Cautions

Use caution in anemia, bronchospasm, cardiac disease, CHF, HTN, SLE, fluid retention, hepatic/renal impairment, bleeding diathesis

If severe diarrhea occurs, reduce dose or temporarily discontinue drug

Therapy may cause premature closure of ductus arteriosus; avoid use in pregnant women starting at 30 weeks of gestation (third trimester)

Mefenamic acid 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 therapy tapered slowly if a decision is made to discontinue corticosteroid

Drug associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma

Therapy can lead to new onset of hypertension or worsening of pre­existing hypertension, either of which may contribute to increased incidence of CV events; patients taking angiotensin-converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking this medication; monitor blood pressure during initiation of treatment and throughout course of therapy

Increases in serum potassium concentration, including hyperkalemia, reported with use, even in some patients without renal impairment; in patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state

Exacerbation of asthma-related to aspirin sensitivity

• A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm and/or intolerance to aspirin and other NSAIDs
• Because cross-reactivity between aspirin and other NSAIDs has been reported in aspirin-sensitive patients, therapy is contraindicated in patients with this sensitivity
• When drug is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in signs and symptoms of asthma

Cardiovascular thrombotic events

• 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 higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate
• Some observational studies found that increased risk of serious CV thrombotic events began as early as the first weeks of treatment; 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 development of such events throughout entire treatment course, even in 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 increased risk of serious CV thrombotic events associated with NSAID use; the concurrent use of aspirin and an NSAID, such as mefenamic acid, increases risk of serious gastrointestinal (GI) event

Postmyocardial infarction 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 first week of treatment
• Avoid use of mefenamic acid in patients with a recent MI unless benefits are expected to outweigh risk of recurrent CV thrombotic events; if mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia

Hepatotoxicity

• Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) reported
• Rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure reported
• Elevations of ALT or AST (less than three times ULN) may occur
• Inform patients of warning signs and symptoms of hepatotoxicity (eg, nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms)
• If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), discontinue therapy immediately, and perform a clinical evaluation of the patient

Renal toxicity

• Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury
• Renal toxicity also seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion; in these patients, administration of an NSAID 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly
• Discontinuation of therapy is usually followed by recovery to pretreatment state; no information is available from controlled clinical studies regarding use of mefenamic acid in patients with advanced renal disease
• The renal effects of mefenamic acid may hasten progression of renal dysfunction in patients with pre-existing renal disease; correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid
• Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid
• Avoid use of mefenamic acid in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function
• If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function

Serious skin reactions

• Therapy can cause serious skin adverse reactions such as drug reaction with eosinophilia and systemic symptoms exfoliative dermatitis (DRESS), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal
• Drug Reaction reported in patients taking NSAIDs; 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
• 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 therapy and evaluate the patient immediately
• These serious events may occur without warning; inform patients about the signs and symptoms of serious skin reactions and to discontinue use of mefenamic acid at first appearance of skin rash or any other sign of hypersensitivity
• Therapy is contraindicated in patients with previous serious skin reactions to NSAIDs

Hematologic toxicity

• Anemia has occurred in NSAID-treated patients; this may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis
• If a patient has any signs or symptoms of anemia, monitor hemoglobin or hematocrit; therapy may increase risk of bleeding events
• Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) may increase this risk; monitor for signs of bleeding

Heart Failure(HF) risk

• NSAIDS have the potential to trigger HF by prostaglandin inhibition that leads to sodium and water retention, increased systemic vascular resistance, and blunted response to diuretics
• Fluid retention and edema may occur
• Therapy may blunt CV effects of several therapeutic agents used to treat medical conditions (eg, diuretics, ACE inhibitors, or angiotensin receptor blockers)
• Avoid therapy in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure; if drug is used in patients with severe heart failure, monitor patients for signs of worsening heart failure
• NSAIDS should be avoided or withdrawn whenever possible
• AHA/ACC Heart Failure Guidelines; Circulation. 2016; 134

Risk factors for GI bleeding, ulceration, and perforation

• Even short-term NSAID therapy is not without risk
• Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs reported to ahve 10-fold increased risk for developing a GI bleed compared to patients without these risk factors
• Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status
• Most postmarketing reports of fatal GI events have occurred in elderly or debilitated patients; patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding

• Strategies to minimize GI risks in NSAID-treated patients

  • Use lowest effective dosage for the shortest possible duration
  • Avoid administration of more than one NSAID at a time
  • Avoid use in patients at higher risk unless benefits are expected to outweigh increased risk of bleeding
  • For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs
  • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy
  • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue mefenamic acid until a serious GI adverse event is ruled out
  • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding

Pregnancy

Use of NSAIDs can cause premature closure of 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 to between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy

Use of NSAIDs, including mefenamic acid, at about 30 weeks gestation or later in pregnancy increases risk of premature closure of the fetal ductus arteriosus.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in first or second trimesters of pregnancy are inconclusive; based on animal data, prostaglandins have been shown to have important role in endometrial vascular permeability, blastocyst implantation, and decidualization

Animal data

• In animal studies, administration of prostaglandin synthesis inhibitors such as mefenamic acid, resulted in increased pre- and post-implantation loss
• Prostaglandins also have been shown to have 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
• Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs can cause premature closure of fetal ductus arteriosus
• If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit use to lowest effective dose and shortest duration possible; if mefenamic acid treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice

Labor and delivery

• In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, decreased pup survival occurred and increased the incidence of stillbirth’ the effects of mefenamic acid on labor and delivery in pregnant women are unknown

Infertility

• Based on the mechanism of action, use of prostaglandin-mediated NSAIDs, including mefenamic acid may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women
• Published animal studies have shown that administration of prostaglandin synthesis inhibitors has potential to disrupt prostaglandin in mediated follicular rupture required for ovulation; small studies in women treated with NSAIDs have also shown a reversible delay in ovulation; consider withdrawal of NSAIDs, including mefenamic acid, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Lactation

Trace amounts of mefenamic acid may be present in breast milk and transmitted to nursing infant; because of potential for serious adverse reactions in nursing infants from mefenamic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account importance of drug to mother

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits synthesis of prostaglandins in body tissues by inhibiting at least 2 cyclooxygenase isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2)

May inhibit chemotaxis, may alter lymphocyte activity, decrease proinflammatory cytokine activity, and may inhibit neutrophil aggregation. These effects may contribute to its anti-inflammatory activity

Pharmacokinetics

Half-life: 2 hr

Onset: Rapid

Peak Plasma Time: 2-4 hr (1 g dose); reached by the second day of administration (1 g dose, 4x daily)

Peak Plasma Concentration: 10 mcg/mL (1 g dose); 20 mcg/mL (1 g dose, 4x daily)

Protein Bound: Extensive

Metabolism: Hepatic oxidation/conjugation

Metabolites: 3'-hydroxymethyl and 3'-carboxyl acid metabolites and their glucuronic acid conjugates

Enzymes inhibited: Cyclooxygenase

Excretion: urine 66% (single dose); feces 20-25%

Dialyzable: No