Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and
nonselective NSAIDs of up to three 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 mefenamic
acid, increases the risk of serious gastrointestinal (GI) events (see WARNINGS;
Gastrointestinal Bleeding, Ulceration, and Perforation).
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 10-14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS).
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 four years of follow-up.
Avoid the use of mefenamic acid in patients with a recent
MI unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If mefenamic acid is used in patients with a recent MI,
monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including mefenamic acid, cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, 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 3-6 months, and in
about 2-4% of patients treated for one year. However, even short-term NSAID
therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And Perforation
Patients with a prior history of peptic ulcer disease
and/or GI bleeding who used NSAIDs had a greater than 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 occurred in elderly or
debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated
- Use the lowest effective dosage for the shortest possible
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are
expected to outweigh the increased risk of bleeding. For such patients, as well
as those with active GI bleeding, consider alternate therapies other than
- 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 (see PRECAUTIONS DRUG INTERACTIONS).
Elevations of ALT or AST (three or more times the upper
limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated
patients in clinical trials. In addition, rare, sometimes fatal, cases of
severe hepatic injury, including fulminant hepatitis, liver necrosis, and
hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may
occur in up to 15% of patients treated with NSAIDs including mefenamic acid.
Inform patients of the warning signs and symptoms of hepatotoxicity
(e.g., 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 (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately,
and perform a clinical evaluation of the patient.
NSAIDs, including mefenamic acid, can lead to new onset
of hypertension or worsening of preexisting hypertension, either of which may
contribute to the 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 NSAIDs (see PRECAUTIONS: DRUG INTERACTIONS).
Monitor blood pressure (BP) 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
two-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 mefenamic acid 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 PRECAUTIONS: DRUG INTERACTIONS).
Avoid the use of mefenamic acid in patients with severe
heart failure unless the benefits are expected to outweigh the risk of
worsening heart failure. If mefenamic acid is used in patients with severe
heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
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 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 NSAID
therapy is usually followed by recovery to the pretreatment state. No
information is available from controlled clinical studies regarding the use of
mefenamic acid in patients with advanced renal disease. The renal effects of
mefenamic acid may hasten the 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 (see PRECAUTIONS: DRUG INTERACTIONS).
Avoid the use of mefenamic acid in patients with advanced renal disease unless
the benefits are expected to outweigh the risk of worsening renal function. If
mefenamic acid is used in patients with advanced renal disease, monitor
patients for signs of worsening renal function.
Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects
have been attributed to a hyporeninemic-hypoaldosteronism state.
Mefenamic acid has been associated with anaphylactic
reactions in patients with and without known hypersensitivity to mefenamic acid
and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS;
Exacerbation of Asthma Related to Aspirin Sensitivity).
Seek emergency help if anaphylactic reaction occurs.
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 such aspirin-sensitive patients, mefenamic acid is
contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS).
When mefenamic acid is used in patients with pre-existing asthma (without known
aspirin sensitivity), monitor patients for changes in the signs and symptoms of
Serious Skin Reactions
NSAIDs, including mefenamic acid, can cause serious skin
adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious
events may occur without warning. Inform patients about the signs and symptoms
of serious skin reactions and to discontinue the use of mefenamic acid at the
first appearance of skin rash or any other sign of hypersensitivity. Mefenamic
acid is contraindicated in patients with previous serious skin reactions to
NSAIDs (see CONTRAINDICATIONS).
Premature Closure Of Fetal Ducts Arteriosus
Mefenamic acid may cause premature closure of the ductus
arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnant women
starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy).
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 treated with mefenamic acid has any
signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including mefenamic acid, may increase the risk
of bleeding events. Co-morbid conditions such as coagulation disorders or
concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g.,
aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine
reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for
signs of bleeding (see PRECAUTIONS: DRUG INTERACTIONS).