Mefenamic Acid

Name: Mefenamic Acid

Brand names

  • Ponstel®

Warnings

Black Box Warnings

Cardiovascular risk

  • NSAIDs may increase risk of serious cardiovascular thrombotic events, myocardial infarction (MI), & stroke, which can be fatal
  • Risk may increase with duration of use
  • Patients with risk factors for or existing cardiovascular disease may be at greater risk
  • NSAIDs are contraindicated for perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (increased risk of MI & stroke)

Gastrointestinal risk

  • NSAIDs increase risk of serious GI adverse events including bleeding, ulceration, & perforation of the stomach or intestines, which can be fatal
  • GI adverse events may occur at any time during use & without warning symptoms
  • Elderly patients are at greater risk for serious GI events

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

Long-term administration of NSAIDs may result in renal papillary necrosis and other renal injury; patients at greatest risk include the elderly, or those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, and individuals taking diuretics, ACE inhibitors, or ARBs

History of: peptic ulcer, GI bleeding, upper GI disease

If severe diarrhea occurs, reduce dose or temporarily discontinue drug

Risk of serious skin reactions

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
  • NSAIDS should be avoided or withdrawn whenever possible
  • AHA/ACC Heart Failure Guidelines; Circulation. 2016; 134

Pregnancy & Lactation

Pregnancy Category: C; D if used for prolonged periods, or near term (premature closure of ductus arteriosus)

The Quebec Pregnancy Registry identified 4705 women who had spontaneous abortions by 20 weeks' gestation; each case was matched to 10 control subjects (n=47,050) who had not had spontaneous abortions; exposure to nonaspirin NSAIDs during pregnancy was documented in approximately 7.5% of cases of spontaneous abortions and in approximately 2.6% of controls. (CMAJ, September 6, 2011; DOI:10.1503/cmaj.110454)

Lactation: contraindicated; excreted in breast milk

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.

Mefenamic acid dosing information

Usual Adult Dose for Pain:

Initial dose: 500 mg orally once
Following initial dose: 250 mg orally every 6 hours as needed
Duration of therapy: Usually not to exceed 1 week

Use: For the relief of acute pain

Usual Adult Dose for Dysmenorrhea:

Initial dose: 500 mg orally once
Following initial dose: 250 mg orally every 6 hours as needed
Duration of therapy: 2 to 3 days

Comments:
-Treatment should begin at the onset of bleeding and associated symptoms.

Use: For the treatment of primary dysmenorrhea

Usual Pediatric Dose for Pain:

14 years or older:
-Initial dose: 500 mg orally once
-Following initial dose: 250 mg orally every 6 hours as needed
-Duration of therapy: Usually not to exceed 1 week

Use: For the relief of acute pain

Usual Pediatric Dose for Dysmenorrhea:

14 years or older:
-Initial dose: 500 mg orally once
-Following initial dose: 250 mg orally every 6 hours as needed
-Duration of therapy: 2 to 3 days

Comments:
-Treatment should begin at the onset of bleeding and associated symptoms.

Use: For the treatment of primary dysmenorrhea

What other drugs will affect mefenamic acid?

Ask your doctor before using mefenamic acid if you take an antidepressant such as citalopram, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, or vilazodone. Taking any of these medicines with an NSAID may cause you to bruise or bleed easily.

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • lithium;

  • methotrexate;

  • antacids such as Milk of Magnesia, Maalox, Mylanta, or Rolaids;

  • a blood thinner (warfarin, Coumadin, Jantoven);

  • heart or blood pressure medication, including a diuretic or "water pill"; or

  • steroid medicine (such as prednisone).

This list is not complete. Other drugs may interact with mefenamic acid, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Introduction

Prototypical NSAIA; anthranilic acid derivative (fenamate); structurally and pharmacologically related to meclofenamate sodium.125 a

Uses of Mefenamic Acid

  • It is used to ease pain.
  • It is used to ease painful period (menstrual) cycles.
  • It may be given to you for other reasons. Talk with the doctor.

What do I need to tell my doctor BEFORE I take Mefenamic Acid?

  • If you have an allergy to mefenamic acid or any other part of mefenamic acid.
  • If you have an allergy to aspirin or NSAIDs.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: GI (gastrointestinal) swelling, kidney disease, or ulcer disease.
  • If you have GI (gastrointestinal) bleeding.
  • If you are having trouble getting pregnant or you are having your fertility checked.
  • If you are pregnant or may be pregnant. Do not take this medicine if you are in the third trimester of pregnancy. You may also need to avoid mefenamic acid at other times during pregnancy. Talk with your doctor to see when you need to avoid taking this medicine during pregnancy.
  • If you are breast-feeding or plan to breast-feed.
  • If you are taking any other NSAID.
  • If you are taking a salicylate drug like aspirin.
  • If you are taking pemetrexed.

This is not a list of all drugs or health problems that interact with mefenamic acid.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Mefenamic Acid Description

Mefenamic Acid Capsules are a member of the fenamate group of nonsteroidal anti- inflammatory drugs (NSAIDs). Each Size '1' Yellow-Yellow capsule, with 'ML' imprinted on the cap & '250' imprinted on the body, 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 2 and the structural formula of Mefenamic Acid is:


Each capsule also contains lactose monohydrate. The capsule shell contains D&C yellow No. 10; FD&C blue No. 1; FD&C red No. 3; FD&C yellow No. 6; gelatin, sodium lauryl sulfate, titanium dioxide, black iron oxide, propylene glycol & shellac.

Mefenamic Acid - Clinical 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 (Vzss/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) .


TABLE 1. Pharmacokinetic Parameter Estimates for Mefenamic Acid


PK Parameters
Normal Healthy Adults (18 to 45 yr)
 
Value
CV
T max (hr)
2
66
Oral clearance (L/hr)
21.13
38
Apparent volume of distribution; Vz/F (L/kg)
1.06
60
Half-life; t ½ (hrs)
2 to 4
N/A

 

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 max in 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 ( seeWARNINGS; 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.

Precautions

General

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 their therapy tapered slowly if a decision is made to discontinue corticosteroids.

Information for Patients

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


Advise patients to stop Mefenamic Acid immediately if they develop any type of rash and contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions).


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 closure of the fetal ductus arteriosus (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus).


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 riskofgastrointestinaltoxicity,and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, PRECAUTIONS; Drug Interactions).Alertpatients that NSAIDsmay be present in “over the counter” medications for treatment of colds, fever, or insomnia.


Use of NSAIDS and Low-Dose Aspirin


Informpatientsnot to use low-dose aspirin concomitantly with Mefenamic Acid until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions).

 

Masking of Inflammation and Fever


The pharmacological activity of Mefenamic Acid in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile checked periodically (see   WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation, and Hepatotoxicity ).

Drug Interactions

See Table 2 for clinically significant drug interactions with Mefenamic Acid.

 

Table 2: Clinically Significant Drug Interactions with Mefenamic Acid

 

Drugs That Interfere with Hemostasis
Clinical Impact:
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.
Intervention:
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) .
Aspirin
Clinical Impact:
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) .
Intervention:
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.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
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.
Intervention:
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.
Diuretics
Clinical Impact:
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.
Intervention
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).
Digoxin
Clinical Impact:
The concomitant use of Mefenamic Acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:
During concomitant use of Mefenamic Acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:
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.
Intervention:
During concomitant use of Mefenamic Acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:
During concomitant use of Mefenamic Acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:
Concomitant use of Mefenamic Acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:
During concomitant use of Mefenamic Acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:
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 andPerforation).
Intervention:
The concomitant use of Mefenamic Acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:
Concomitant use of Mefenamic Acid and pemetrexed may increase the risk of pemetrexed­associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:
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.
Antacid
Clinical Impact:
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 C max and AUC of Mefenamic Acid by 125% and 36%, respectively.
Intervention:
Concomitant use of Mefenamic Acid and antacids is not generally recommended because of possible increased adverse events.

Drug/Laboratory Test Interactions

Mefenamic Acid may prolong prothrombin time. Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary.


A false-positive reaction for urinary bile, using the diazo tablet test, may result after Mefenamic Acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis


Long-term studies in animals to evaluate the carcinogenic potential of Mefenamic Acid have not been conducted.


Mutagenesis


Studies to evaluate the mutagenic potential of Mefenamic Acid have not been completed.

 

Impairment of Fertility


Dietary administration of Mefenamic Acid to male rats 61 days- and to female rats 15 days- prior to mating through to Gestation Day (GD) 21 at a dose of 155 mg/kg/day (equivalent to the Maximum Recommended Human Dose [MRHD] of 1500 mg/day on a mg/m 2 basis) resulted in decreased corpora lutea.


In another study, rats administered up to 10-times a human dose of 250 mg showed decreased fertility.

Pregnancy

Risk Summary


Use of  NSAIDs, including Mefenamic Acid, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Mefenamic Acid, in pregnant women starting at 30 weeks of gestation (third trimester) (see WARNINGS; Premature Closure of Fetal Ductus Arterious).

There are no adequate and well-controlled studies of Mefenamic Acid in pregnant women.


Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies in rats and rabbits when dosed throughout gestation, there were no evidence of developmental effects at a dose of Mefenamic Acid 1.6-times and 0.6-times the maximum recommended human dose (MRHD), respectively. Dietary administration of Mefenamic Acid at a dose 1.2-times the MRHD from gestation day (GD) 15 to weaning or at a dose equivalent to the MRHD from 15 days prior to mating through to weaning resulted in greater incidences of perinatal death [see Data]. 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 Mefenamic Acid, resulted in increased pre- and post-implantation loss.


Data


Animal data


Pregnant rats administered 249 mg/kg of Mefenamic Acid (1.6-times the MRHD of 1500 mg/day on a mg/m 2 basis) from GD 6 to GD 15 did not result in any clear adverse developmental effects.


Pregnant rabbits given 50 mg/kg of Mefenamic Acid (0.6-times the MRHD on a mg/m 2 basis) from GD 6 to GD 18 did not result in any clear treatment-related adverse developmental effects. However, incidences of resorption were greater in treated compared to control animals. This dose was associated with some evidence of maternal toxicity with 4 of 18 rabbits exhibiting diarrhea and weight loss.


Dietary administration of Mefenamic Acid at a dose of 181 mg/kg (1.2-times the MRHD on a mg/m 2 basis) to pregnant rats from GD 15 to weaning resulted in an increased incidence of perinatal death. Treated dams were associated with decreased weight gain and delayed parturition. In another study, dietary administration of Mefenamic Acid at a dose of 155 mg/kg (equivalent to the MRHD of 1500 mg/day on a mg/m 2 basis) to females 15 days prior to mating through to weaning resulted in smaller average litter sizes and higher incidence of perinatal death.

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.

Nursing Mothers

Trace amounts of Mefenamic Acid may be present in breast milk and transmitted to the nursing infant. Because of the 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 the importance of the drug to the mother.

Infertility

Females


Based on the mechanism of action, the 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 the 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.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 14 have not been established.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see  WARNINGS; Cardiovascular Thrombotic Events, Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia,PRECAUTIONS; Laboratory Monitoring).

Clinicalstudies of Mefenamic Acid did notinclude sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any NSAID, caution should be exercised in treating the elderly (65 years and older).


This drug is known to besubstantially excreted by the kidney, and the riskof toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (See CLINICALPHARMACOLOGY, ADVERSEREACTIONS).

Mefenamic Acid 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.

Special Populations Hepatic Function Impairment

The potential exists for mefenamic acid metabolites to accumulate.

Use Labeled Indications

Pain, mild to moderate: Relief of mild to moderate pain in patients ≥14 years, when therapy will not exceed 1 week.

Primary dysmenorrhea: Treatment of primary dysmenorrhea.

Contraindications

Hypersensitivity to mefenamic acid, or any component of the formulation; use in the setting of coronary artery bypass graft (CABG) surgery; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.

Canadian labeling: Additional contraindications (not in US labeling): Pregnancy (third trimester); breast-feeding; severe uncontrolled heart failure; active gastric, duodenal, or peptic ulcer; active gastrointestinal bleeding; cerebrovascular bleeding or other bleeding disorders; inflammatory bowel disease; severe hepatic impairment or active hepatic disease; severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease; known hyperkalemia; adolescents <18 years of age

Dosing Renal Impairment

Avoid use in patients with preexisting renal disease and in patients with advanced renal disease.

KDIGO 2012 guidelines provide the following recommendations for NSAIDs:

eGFR 30 to <60 mL/minute/1.73 m2: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury.

eGFR <30 mL/minute/1.73 m2: Avoid use.

Adverse Reactions

1% to 10%:

Central nervous system: Dizziness (3% to 9%), headache, nervousness

Dermatologic: Pruritus, skin rash

Endocrine & metabolic: Fluid retention

Gastrointestinal: Abdominal cramps, abdominal distress, abdominal pain, constipation, diarrhea, duodenal ulcer (with bleeding or perforation), dyspepsia, flatulence, gastric ulcer (with bleeding or perforation), gastritis, heartburn, nausea, vomiting

Hematologic & oncologic: Hemorrhage

Hepatic: Increased liver enzymes

Otic: Tinnitus

<1% (Limited to important or life-threatening): Acute renal failure, agranulocytosis, allergic rhinitis, anemia, angioedema, aseptic meningitis, auditory impairment, blurred vision, bone marrow depression, cardiac arrhythmia, cardiac failure, confusion, conjunctivitis, cystitis, depression, drowsiness, dyspnea, epistaxis, erythema multiforme, gastrointestinal ulcer, hallucination, hemolytic anemia, hepatitis, hepatotoxicity (idiosyncratic; Chalasani 2014), hot flash, hypertension, insomnia, leukopenia, peripheral neuropathy, polydipsia, polyuria, Stevens-Johnson syndrome, stomatitis, tachycardia, thrombocytopenia, toxic amblyopia, toxic epidermal necrolysis, urticaria, xerophthalmia

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy.

• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention; use with caution in patients with edema. Avoid use in heart failure (ACCF/AHA [Yancy, 2013]). Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• GI events: [US Boxed Warning]: NSAIDs cause increased risk of serious GI inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt, 2008).

• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal) severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if clinical signs or symptoms of hepatic disease develop or if systemic manifestations occur.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.

• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics, ACE inhibitors, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.

• Skin reactions: NSAIDs may cause potentially fatal skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first appearance of skin rash (or any other sign of hypersensitivity).

Disease-related concerns:

• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.

• Coronary artery bypass graft surgery: [US Boxed Warning]: Use is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustments may be necessary due to extensive hepatic metabolism. Patients with advanced hepatic disease are at an increased risk of GI bleeding with NSAIDs.

• Renal impairment: Avoid use in patients with preexisting renal disease and in patients with advanced renal disease; monitor renal function closely if therapy must be initiated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience heartburn, nausea, vomiting, diarrhea, constipation, or flatulence. Have patient report immediately to prescriber signs of abdominal ulcers (severe abdominal or back pain; black, tarry, or bloody stools; vomiting blood or vomit that looks like coffee grounds; or weight gain or abnormal swelling), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling), shortness of breath, excessive weight gain, swelling of arms or legs, angina, tachycardia, severe headache, severe dizziness, passing out, severe loss of strength and energy, tinnitus, mood changes, depression, severe abdominal pain, vision changes, severe back pain, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Dose Adjustments

Preexisting renal disease: Contraindicated

Precautions

US BOXED WARNINGS: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS:
-Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
-This drug is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
-NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at a greater risk for serious GI events.

Safety and efficacy have not been established in patients younger than 14 years.

Consult WARNINGS section for additional precautions.

Other Comments

Administration advice:
-Take orally with food or milk.

General:
-Prior to initiating treatment, the potential benefits and risks of this drug should be weighed against other treatment options.
-The lowest effective dose for the shortest duration consistent with individual patient treatment goals should be used.
-There is an increased risk of heart attack, heart failure, and stroke when taking nonsteroidal anti-inflammatory drugs (NSAIDs); these events may occur at any time during treatment and risk increases with long term use, a history of cardiovascular (CV) disease or risk factors for CV disease, and higher doses.

Monitoring:
-Cardiovascular: Monitor blood pressure closely during initiation and throughout course of therapy.
-Gastrointestinal: Monitor for signs/symptoms of gastrointestinal bleeding.
-Renal function: Monitor renal status, especially in patients with conditions where renal prostaglandins have a supportive role in the maintenance of renal perfusion.
-Monitor blood counts, renal, and hepatic function periodically for patients receiving long-term therapy.

Patient advice:
-Patients should seek medical advice for signs and symptoms of gastrointestinal events, adverse skin reactions, allergic reactions, hepatotoxicity, or unexplained weight gain or edema.
-Patients should seek medical attention immediately if signs/symptoms of cardiovascular events occur including, shortness of breath, slurred speech, chest pain, or weakness on one side of the body.
-Patients should talk to their health care provider if they are pregnant, planning to become pregnant, or breastfeeding; this drug should not be used during pregnancy at 30 weeks gestation or later.

(web3)