Indications and Usage
Carefully consider the potential benefits and risks of mefenamic acid capsules and other treatment options before deciding to use mefenamic acid capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).
Mefenamic acid capsules are indicated:
- For relief of mild to moderate pain in patients ≥14 years of age, when therapy will not exceed one week (7 days).
- For treatment of primary dysmenorrhea.
Dosage and Administration
Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see Warnings; Gastrointestinal Bleeding, Ulceration, and Perforation).
After observing the response to initial therapy with mefenamic acid, the dose and frequency should be adjusted to suit an individual patient's needs.
For the relief of acute pain in adults and adolescents ≥14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week.
For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, given orally, starting with the onset of bleeding and associated symptoms. Clinical studies indicate that effective treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days.
Contraindications
Mefenamic acid capsules are contraindicated in the following patients:
- Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to mefenamic acid or any components of the drug product (see WARNINGS; Anaphylactic Reactions, Serious Skin Reactions).
- History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients (see WARNINGS; Anaphylactic Reaction, Exacerbation of Asthma Related to Aspirin Sensitivity).
- In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS; Cardiovascular Thrombotic Events).
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiovascular Thrombotic Events (see Warnings)
- GI Bleeding, Ulceration and Perforation (see Warnings)
- Hepatotoxicity (see Warnings)
- Hypertension (see Warnings)
- Heart Failure and Edema (see Warnings)
- Renal Toxicity and Hyperkalemia (see Warnings)
- Anaphylactic Reactions (see Warnings)
- Serious Skin Reactions (see Warnings)
- Hematologic Toxicity (see Warnings)
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In patients taking mefenamic acid or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are:
Gastrointestinal experiences including - abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting, abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, tinnitus
Additional adverse experiences reported occasionally and listed here by body system include:
Body as a whole
Fever, infection, sepsis
Cardiovascular system
Congestive heart failure, hypertension, tachycardia, syncope
Digestive system
Dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice
Hemic and lymphatic system
Ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia
Metabolic and nutritional
Weight changes
Nervous system
Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness; insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory system
Asthma, dyspnea
Skin and appendages
Alopecia, photosensitivity, pruritus, sweat
Special senses
Blurred vision
Urogenital system
Cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Other adverse reactions, which occur rarely are:
Body as a whole
Anaphylactoid reactions, appetite changes, death
Cardiovascular system
Arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis
Digestive system
Eructation, liver failure, pancreatitis
Hemic and lymphatic system
Agranulocytosis, hemolytic anemia, aplastic anemia, lymph-adenopathy, pancytopenia
Metabolic and nutritional
Hyperglycemia
Nervous system
Convulsions, coma, hallucinations, meningitis.
Respiratory
Respiratory depression, pneumonia
Skin and appendages
Angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special senses
Conjunctivitis, hearing impairment
Drug Interactions
See Table 2 for clinically significant drug interactions with mefenamic acid.
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Drugs That Interfere with Hemostasis
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Clinical Impact:
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Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Intervention:
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Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
(see
Warnings;
Hematologic Toxicity)
.
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Aspirin
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Clinical Impact:
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone
(see
Warnings;
Gastrointestinal Bleeding, Ulceration and Perforation)
.
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Intervention:
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Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see
Warnings;
Hematologic Toxicity).
Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. |
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ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
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Clinical Impact:
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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Intervention:
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During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see Warnings; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Diuretics
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Clinical Impact:
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
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Intervention
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During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects
(see
Warnings;
Renal Toxicity and Hyperkalemia).
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Digoxin
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Clinical Impact:
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The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
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Intervention:
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During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
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Lithium
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Clinical Impact:
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance
.The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
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Intervention:
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During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
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Methotrexate
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Clinical Impact:
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
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Intervention:
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During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
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Cyclosporine
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Clinical Impact:
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Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine's nephrotoxicity.
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Intervention:
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During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
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NSAIDs and Salicylates
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Clinical Impact:
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Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy
(see
Warnings;
Gastrointestinal Bleeding, Ulceration and Perforation).
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Intervention:
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The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
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Pemetrexed
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Clinical Impact:
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Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
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Intervention:
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During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Antacid
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Clinical Impact:
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In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively.
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Intervention:
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Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.
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Overdosage
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (see Warnings; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia).
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).
Description
Mefenamic acid is a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each ivory capsule contains 250 mg of mefenamic acid for oral administration. Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230° to 231°C and water solubility of 0.004% at pH 7.1. The chemical name is N-2,3-xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C 15H 15NO 2and the structural formula of mefenamic acid is:
Each capsule also contains lactose monohydrate and magnesium stearate. The capsule shell contains gelatin, sodium lauryl sulfate, titanium dioxide, D&C yellow No. 10, FD&C yellow No. 6 and FD&C red No. 3.
image-01Clinical Pharmacology
Mechanism of Action
Mefenamic acid has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of mefenamic acid, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).
Mefenamic acid is a potent inhibitor of prostaglandin synthesis in vitro. Mefenamic acid concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because mefenamic acid is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
Pharmacokinetics
Absorption
Mefenamic acid is rapidly absorbed after oral administration. In two 500-mg single oral dose studies, the mean extent of absorption was 30.5 mcg/hr/mL (17%CV). The bioavailability of the capsule relative to an IV dose or an oral solution has not been studied.
Following a single 1-gram oral dose, mean peak plasma levels ranging from 10 to 20 mcg/mL have been reported. Peak plasma levels are attained in 2 to 4 hours and the elimination half-life approximates 2 hours. Following multiple doses, plasma levels are proportional to dose with no evidence of drug accumulation. In a multiple dose trial of normal adult subjects (n=6) receiving 1-gram doses of mefenamic acid four times daily, steady-state concentrations of 20 mcg/mL were reached on the second day of administration, consistent with the short half-life.
The effect of food on the rate and extent of absorption of mefenamic acid has not been studied. Concomitant ingestion of antacids containing magnesium hydroxide has been shown to significantly increase the rate and extent of mefenamic acid absorption (see Precautions; Drug Interactions) .
Distribution
Mefenamic acid has been reported as being greater than 90% bound to albumin. The relationship of unbound fraction to drug concentration has not been studied. The apparent volume of distribution (Vz ss/F) estimated following a 500-mg oral dose of mefenamic acid was 1.06 L/kg.
Based on its physical and chemical properties, mefenamic acid is expected to be excreted in human breast milk (see Precautions; Nursing Mothers).
Elimination
Metabolism:
Mefenamic acid is metabolized by cytochrome P450 enzyme CYP2C9 to 3-hydroxymethyl mefenamic acid (Metabolite I). Further oxidation to a 3-carboxymefenamic acid (Metabolite II) may occur. The activity of these metabolites has not been studied. The metabolites may undergo glucuronidation and mefenamic acid is also glucuronidated directly. A peak plasma level approximating 20 mcg/mL was observed at 3 hours for the hydroxy metabolite and its glucuronide (n=6) after a single 1-gram dose. Similarly, a peak plasma level of 8 mcg/mL was observed at 6 to 8 hours for the carboxy metabolite and its glucuronide.
Excretion:
Approximately fifty-two percent of a mefenamic acid dose is excreted into the urine primarily as glucuronides of mefenamic acid (6%), 3-hydroxymefenamic acid (25%) and 3-carboxymefenamic acid (21%). The fecal route of elimination accounts for up to 20% of the dose, mainly in the form of unconjugated 3-carboxymefenamic acid.
The elimination half-life of mefenamic acid is approximately two hours. Half-lives of metabolites I and II have not been precisely reported, but appear to be longer than the parent compound. The metabolites may accumulate in patients with renal or hepatic failure. The mefenamic acid glucuronide may bind irreversibly to plasma proteins. Because both renal and hepatic excretions are significant pathways of elimination, dosage adjustments in patients with renal or hepatic dysfunction may be necessary. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (see Warnings; Renal Toxicity and Hyperkalemia).
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PK
Parameters
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Normal
Healthy
Adults
( 18 to 45 yr ) |
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Value
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CV
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| T
m
a
x(hr)
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2
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66
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| Oral clearance (L/hr)
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21.13
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38
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| Apparent volume of distribution; Vz/F (L/kg)
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1.06
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60
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| Half-life; t ½ (hrs)
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2 to 4
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N/A
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Special Populations
Pediatric:
Mefenamic acid has not been adequately investigated in pediatric patients less than 14 years of age. A study in 17 preterm infants administered 2 mg/kg indicated that the half-life was about five times as long as adults, consistent with the low activity of metabolic enzymes in newborn infants. The mean C maxin this study was 4 mcg/mL (range 2.9 to 6.1). The mean time to maximum concentration (T max) was 8 hours (range 2 to 18 hours).
Race:
Pharmacokinetic differences due to race have not been identified.
Hepatic Impairment:
Mefenamic acid pharmacokinetics have not been studied in patients with hepatic dysfunction. As hepatic metabolism is a significant pathway of mefenamic acid elimination, patients with acute and chronic hepatic disease may require reduced doses of mefenamic acid compared to patients with normal hepatic function (see WARNINGS; Hepatotoxicity).
Renal Impairment:
Mefenamic acid pharmacokinetics have not been investigated in subjects with renal insufficiency. Given that mefenamic acid, its metabolites and conjugates are primarily excreted by the kidneys, the potential exists for mefenamic acid metabolites to accumulate. Mefenamic acid should not be administered to patients with pre-existing renal disease or in patients with significantly impaired renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
Drug Interaction Studies
Aspirin:
When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see Precautions; Drug Interactions).
Clinical Studies
In controlled, double-blind, clinical trials, mefenamic acid was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either mefenamic acid, 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Mefenamic acid was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated.
Clinical Studies
In controlled, double-blind, clinical trials, mefenamic acid was evaluated for the treatment of primary spasmodic dysmenorrhea. The parameters used in determining efficacy included pain assessment by both patient and investigator; the need for concurrent analgesic medication; and evaluation of change in frequency and severity of symptoms characteristic of spasmodic dysmenorrhea. Patients received either mefenamic acid, 500 mg (2 capsules) as an initial dose of 250 mg every 6 hours, or placebo at onset of bleeding or of pain, whichever began first. After three menstrual cycles, patients were crossed over to the alternate treatment for an additional three cycles. Mefenamic acid was significantly superior to placebo in all parameters, and both treatments (drug and placebo) were equally tolerated.
How Supplied / Storage and Handling
Mefenamic acid capsules USP, 250 mg are available as size '1' capsules having ivory cap and ivory body imprinted with "LU" on cap and "R31" on body in black ink, containing white to off white granular powder.
They are supplied as follows:
Bottles of 30 Capsules NDC 80425-0423-01
Bottles of 60 Capsules NDC 80425-0423-02
Bottles of 90 Capsules NDC 80425-0423-03
Dispense in a tight container as defined in the USP.
Storage:
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Manufactured for:
Lupin Pharmaceuticals, Inc.
Baltimore, Maryland 21202
United States
Manufactured by:
Lupin Limited
Goa 403 722
INDIA
Revised: June 2021 ID#: 267984
Distributed by:
Advanced Rx of Tennessee, LLC
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families and their caregivers of the following information before initiating therapy with mefenamic acid and periodically during the course of ongoing therapy.
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; Cardiovascular Thrombotic Events).
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding (see Warnings; Gastrointestinal Bleeding, Ulceration, and Perforation).
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop mefenamic acid and seek immediate medical therapy (see WARNINGS; Hepatotoxicity).
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; Heart Failure and Edema).
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see Contraindications, Warnings; Anaphylactic Reactions).
Serious Skin Reactions, including DRESS
Advise patients to stop mefenamic acid immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see Warnings).
Female Fertility
Advise females of reproductive potential who desire pregnancy that NSAIDs, including mefenamic acid, may be associated with a reversible delay in ovulation. (see Precautions; Carcinogenesis, Mutagenesis, Impairment of Fertility).
Fetal Toxicity
Inform pregnant women to avoid use of mefenamic acid and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus If treatment with mefenamic acid 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 ] .
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see Warnings; Gastrointestinal Bleeding, Ulceration and Perforation, Precautions; Drug Interactions). Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.
Use of NSAIDS and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with mefenamic acid until they talk to their healthcare provider (see Precautions; Drug Interactions).