Mefenamic Acid

Pronunciation

(me fe NAM ik AS id)

U.S. Brand Names

Ponstel®

Generic Available

Canadian Brand Names

Apo-Mefenamic®; Nu-Mefenamic; PMS-Mefenamic Acid; Ponstan®; Ponstel®

Use

Short-term relief of mild to moderate pain including primary dysmenorrhea

Pregnancy Risk Factor

C/D (3rd trimester)

Contraindications

Hypersensitivity to NSAIDs including aspirin or any component of the formulation; pregnancy (3rd trimester)

Warnings/Precautions

Fatal asthmatic and anaphylactoid reactions have occurred in patients with "aspirin triad." Use with caution in patients with CHF, hypertension, dehydration, decreased renal or hepatic function, history of GI disease (bleeding, ulcers, or previous GI symptoms with NSAID use), or those receiving anticoagulants and/or corticosteroids. Use lowest effective dose for shortest period possible; bleeding risk has been correlated to dose and duration of therapy. Gastrointestinal bleeding may occur without prior symptoms of gastrointestinal irritation. Elderly are at a high risk for adverse effects from NSAIDs. As many as 60% of elderly can develop peptic ulceration and/or hemorrhage asymptomatically.

Use of NSAIDs can compromise existing renal function especially when Clcr<30 mL/minute. CNS adverse effects such as confusion, agitation, and hallucination are generally seen in overdose or high-dose situations; however, elderly may demonstrate these adverse effects at lower doses than younger adults. Withhold for at least 4-6 half-lives prior to surgical or dental procedures.

Adverse Reactions

1% to 10%:

Central nervous system: Headache, nervousness, dizziness (3% to 9%)

Dermatologic: Itching, rash

Endocrine & metabolic: Fluid retention

Gastrointestinal: Abdominal cramps, heartburn, indigestion, nausea (1% to 10%), vomiting (1% to 10%), diarrhea (1% to 10%), constipation (1% to 10%), abdominal distress/cramping/pain (1% to 10%), dyspepsia (1% to 10%), flatulence (1% to 10%), gastric or duodenal ulcer with bleeding or perforation (1% to 10%), gastritis (1% to 10%)

Hematologic: Bleeding (1% to 10%)

Hepatic: Elevated LFTs (1% to 10%)

Otic: Tinnitus (1% to 10%)

<1%: CHF, hypertension, arrhythmia, tachycardia, confusion, hallucinations, aseptic meningitis, mental depression, drowsiness, insomnia, urticaria, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, polydipsia, hot flashes, gastritis, GI ulceration, cystitis, polyuria, agranulocytosis, anemia, hemolytic anemia, bone marrow suppression, leukopenia, thrombocytopenia, hepatitis, peripheral neuropathy, toxic amblyopia, blurred vision, conjunctivitis, dry eyes, decreased hearing, acute renal failure, dyspnea, allergic rhinitis, epistaxis, stomatitis

Overdosage/Toxicology

Symptoms of overdose include CNS stimulation, agitation, seizures

Management of NSAID intoxication is primarily supportive and symptomatic. Fluid therapy is commonly effective in managing the hypotension that may occur following an acute NSAIDs overdose, except when this is due to an acute blood loss. Seizures tend to be very short-lived and often do not require drug treatment. Although, recurrent seizures should be treated with I.V. diazepam. Since many of the NSAID undergo enterohepatic cycling, multiple doses of charcoal may be needed to reduce the potential for delayed toxicities.

Drug Interactions

Substrate of CYP2C8/9 (minor); Inhibits CYP2C8/9 (strong)

ACE inhibitors: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Angiotensin II antagonists: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Anticoagulants (warfarin, heparin, LMWHs) in combination with NSAIDs can cause increased risk of bleeding.

Antiplatelet drugs (ticlopidine, clopidogrel, aspirin, abciximab, dipyridamole, eptifibatide, tirofiban) can cause an increased risk of bleeding.

Corticosteroids may increase the risk of GI ulceration; avoid concurrent use.

Cyclosporine: NSAIDs may increase serum creatinine, potassium, blood pressure, and cyclosporine levels; monitor cyclosporine levels and renal function carefully.

CYP2C8/9 substrates: Mefenamic acid may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

Gentamicin and amikacin serum concentrations are increased by indomethacin in premature infants. Results may apply to other aminoglycosides and NSAIDs.

Hydralazine's antihypertensive effect is decreased; avoid concurrent use.

Lithium levels can be increased; avoid concurrent use if possible or monitor lithium levels and adjust dose. Sulindac may have the least effect. When NSAID is stopped, lithium will need adjustment again.

Loop diuretics efficacy (diuretic and antihypertensive effect) is reduced. Indomethacin reduces this efficacy, however, it may be anticipated with any NSAID.

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Avoid use during moderate or high-dose methotrexate (increased and prolonged methotrexate levels). NSAID use during low-dose treatment of rheumatoid arthritis has not been fully evaluated; extreme caution is warranted.

Thiazides antihypertensive effects are decreased; avoid concurrent use.

Verapamil plasma concentration is decreased by diclofenac; avoid concurrent use.

Warfarin's INRs may be increased by piroxicam. Other NSAIDs may have the same effect depending on dose and duration. Monitor INR closely. Use the lowest dose of NSAIDs possible and for the briefest duration.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (due to GI irritation).

Mechanism of Action

Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors

Pharmacodynamics/Kinetics

Onset of action: Peak effect: 2-4 hours

Duration: 6 hours

Protein binding: High

Metabolism: Conjugated hepatically

Half-life elimination: 3.5 hours

Excretion: Urine (50%) and feces as unchanged drug and metabolites

Dosage

Children >14 years and Adults: Oral: 500 mg to start then 250 mg every 4 hours as needed; maximum therapy: 1 week

Dosing adjustment/comments in renal impairment: Not recommended for use

Administration

May be administered with food, milk, or antacids.

Test Interactions

Increased chloride (S), increased sodium (S), positive Coombs' [direct], false-positive urinary bilirubin

Patient Education

If self-administered, use exactly as directed; do not increase dose or frequency. Adverse reactions can occur with overuse. Consult your physician before use if you have hypertension or heart failure. Take with food, milk, or antacids. While using this medication, do not use alcohol, excessive amounts of vitamin C, or salicylate-containing foods (curry powder, prunes, raisins, tea, or licorice), other prescription or OTC medications containing aspirin or salicylate, or other NSAIDs without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience nausea, vomiting, gastric discomfort (frequent mouth care, small, frequent meals, chewing gum, or sucking lozenges may help). GI bleeding, ulceration, or perforation can occur with or without pain. Stop taking medication and report ringing in ears; persistent cramping or stomach pain; unresolved nausea or vomiting; respiratory difficulty or shortness of breath; unusual bruising or bleeding (mouth, urine, stool); skin rash; unusual swelling of extremities; chest pain; or palpitations. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 3rd trimester of pregnancy. Consult prescriber if breast-feeding.

Anesthesia and Critical Care Concerns/Other Considerations

The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) suggest that NSAIDs may be used in combination with opioids in select patients for pain management. Concern about adverse events (increased risk of renal dysfunction, altered platelet function and gastrointestinal irritation) limits its use in patients who have other underlying risks for these events.

In short-term use, NSAIDs vary considerably in their effect on blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema; may precipitate renal failure in dehydrated patients.

Cardiovascular Considerations

In short-term use, NSAIDs vary considerably in their effect on blood pressure. A recent meta-analysis (see References) showed that indomethacin and naproxen had the largest effect on blood pressure. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect. Ibuprofen combined with captopril or losartan may attenuate the antihypertensive effects of ACE inhibition or receptor blockade on sitting or 24-hour ambulatory diastolic blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema. One study showed that NSAID use in elderly patients had an increased risk of hospitalization for heart failure. This study gives compelling reasons to avoid or limit the use of NSAIDs in patients with congestive heart failure, particularly in the elderly population.

Dental Health: Effects on Dental Treatment

NSAID formulations are known to reversibly decrease platelet aggregation via mechanisms different than observed with aspirin. The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®). Recovery of platelet function usually occurs 1-2 days after discontinuation of NSAIDs.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Dizziness is common; may cause nervousness, may rarely cause confusion, hallucination, or depression

Mental Health: Effects on Psychiatric Treatment

May rarely cause agranulocytosis; use caution with clozapine or carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels

Dosage Forms

Capsule: 250 mg

References

Balali-Mood M, Critchley JA, Proudfoot AT, et al, "Mefenamic Acid Overdosage," Lancet , 1981, 2(8234):1354-6.

Brooks PM and Day RO, "Nonsteroidal Anti-inflammatory Drugs - Differences and Similarities," N Engl J Med , 1991, 324(24):1716-25.

Clinch D, Banerjee AK, and Ostick G, "Absence of Abdominal Pain in Elderly Patients With Peptic Ulcer," Age Ageing , 1984, 13(2):120-3.

Clive DM and Stoff JS, "Renal Syndromes Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1984, 310(9):563-72.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

Court H and Volans GN, "Poisoning After Overdose With Nonsteroidal Anti-inflammatory Drugs," Adverse Drug React Acute Poisoning Rev , 1984, 3(1):1-21.

"Drugs for Pain," Med Lett Drugs Ther , 1998, 40(1033):79-84.

Gossinger H, Hruby K, Haubenstock A, et al, "Coma in Mefenamic Acid Poisoning," Lancet , 1982, 2(8294):384.

Graham DY, "Prevention of Gastroduodenal Injury Induced by Chronic Nonsteroidal Anti-inflammatory Drug Therapy," Gastroenterology , 1989, 96(2 Pt 2 Suppl):675-81.

Gurwitz JH, Avorn J, Ross-Degnan D, et al, "Nonsteroidal Anti-Inflammatory Drug-Associated Azotemia in the Very Old," JAMA , 1990, 264(4):471-5.

Hawkey CJ, Karrasch JA, Szczepañski L, et al, "Omeprazole Compared With Misoprostrol for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):727-34.

Heerdink ER, Leufkens HG, Herings RM, et al, "NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics," Arch Intern Med , 1998, 158(10):1108-12.

Hendrickse MT, "Mefenamic Acid Overdose Mimicking Brainstem Stroke," Lancet , 1988, 2(8618):1019.

Hoppmann RA, Peden JG, and Ober SK, "Central Nervous System Side Effects of Nonsteroidal Anti-inflammatory Drugs. Aseptic Meningitis, Psychosis, and Cognitive Dysfunction," Arch Intern Med , 1991, 151(7):1309-13.

Jacobi J, Fraser GL, Coursin DB, et al, "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult," Crit Care Med , 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.

Knodel LC, "Preventing NSAID-Induced Ulcers: The Role of Misoprostol," Consult Pharm , 1989, 4:37-41.

Morgan TO, Anderson A, and Bertram D, "Effect of Indomethacin on Blood Pressure in Elderly People With Essential Hypertension Well Controlled on Amlodipine or Enalapril," Am J Hypertens , 2000, 13(11):1161-7.

Page J and Henry D, "Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients: An Underrecognized Public Health Problem," Arch Intern Med , 2000, 160(6):777-84.

Pope JE, Anderson JJ, and Felson DT, "A Meta-analysis of the Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressure," Arch Intern Med , 1993, 153(4):477-84.

Pounder R, "Silent Peptic Ulceration: Deadly Silence or Golden Silence?" Gastroenterology , 1989, 96(2 Pt 2 Suppl):626-31.

Shipton EA and Muller FO, "Severe Mefenamic Acid Poisoning. A Case Report," S Afr Med J , 1985, 67(20):823-4.

Smolinske SC, Hall AH, Vandenberg SA, et al, "Toxic Effects of Nonsteroid Anti-inflammatory Drugs in Overdose. An Overview of Recent Evidence on Clinical Effects and Dose-Response Relationships," Drug Saf , 1990, 5(4):252-74.

Turnbull AJ, Campbell P, and Hughes JA, "Mefenamic Acid Nephropathy - Acute Renal Failure in Overdose," Br Med J (Clin Res Ed) , 1988, 296(6622):646.

Vale JA and Meredith TJ, "Acute Poisoning Due to Nonsteroidal Anti-inflammatory Drugs," Med Toxicol , 1986, 1(1):12-31.

Verbeeck RK, "Pharmacokinetic Drug Interactions With Nonsteroidal Anti-inflammatory Drugs," Clin Pharmacokinet , 1990, 19(1):44-66.

Yeomans ND, Tulassay Z, Juhasz L, et al, "A Comparison of Omeprazole With Ranitidine for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):719-26.

International Brand Names

Acido Mefenamico® (CL); Acido Mefenamico L.CH.® (CL); Acido Mefenamico MK® (CO); Adco-Mefenamic® (ZA); Alfoxan® (CY); Algex® (CL); Algifemin® (CL); Allogon® (ID); Alpain® (ID); Analspec® (ID); Antalv® (PL); Apo-Mefenamic® (CA); Apo-Mefen® (PL); Asam Mefenamat Indo Pharma® (ID); Asam Mefenamat Landson® (ID); Bafhameritin-M® (JP); Beafemic® (SG); Benostan® (ID); Cetalmic® (ID); Conamic® (TH); Contraflam® (GB); Corstanal® (ID); Coslan® (ES); Datan® (ID); Dolcin® (CL); Dolfenal® (ID); Dolodon® (ID); Dolos® (ID); Dysman® (GB); Dysmen-500® (IN); Dyspen® (TH); Dystan® (ID); Femen® (TH); Fenamic® (TH); Fenamin® (ZA); Fendol® (EG, KW, LB, SY); Flamic® (BD); Gandin® (TH); Gitaramin® (ID); Hexalgesic® (ID); Kemostan® (ID); Lapistan® (ID); Lysalgo® (IT); Manomic® (TH); Mectan® (ID); Medicap® (HK); Medifive® (TH); Mednil® (TH); Mefac® (CY, EG, IE, JO, KW, LB, MT); Mefacit® (PL); Mefast® (ID); Mefa® (TH); Mefe-basan® (CH); Mefenacid® (CH); Mefenamic Acid® (GB); Mefenan® (TH); Mefenix® (SG); Mefen® (TH); Mefic® (AU); Mefinal® (ID); Mefinter® (ID); Mefix® (ID); Melur® (CH); Mephadolor® (CH); Namic® (TH); Napan® (HK); Nichostan® (ID); Nu-Mefenamic (CA); Opistan® (ID); Painnox® (TH); Panamic® (TH); Parkemed® (AT, DE); Pefamic® (TH); Pehastan® (ID); Pinalgesic® (IE); PMS-Mefenamic Acid (CA); Ponac® (ZA); Ponalar® (DE, ID); Ponalgic® (IE); Poncofen® (ID); Pondex® (ID); Pondnadysmen® (TH); Ponmel® (HU, IE); Ponnac® (TH); Ponnesia® (TH); Ponsamic® (ID); Ponstan® (AU, BR, CA, CH, CO, FI, GB, HK, ID, IE, IN, MX, NZ, SG, TH, TR, ZA); Ponstan Forte® (GB, IE, TR, ZA); Ponstelax® (ID); Ponstel® (CA, ZA); Ponstil® (AR); Ponstyl® (FR); Pontacid® (BD); Pontalon YSP® (SG); Pontyl® (SG); Prostan® (TH); Pynamic® (TH); Rolab-Mefenamic Acid® (ZA); Rolan® (TR); Sefmic® (TH); Sicadol® (CL); Solasic® (ID); Spartan® (ID); Spiralgin 500® (CH); Sporsal® (CH); Stanza® (ID); Stelpon® (ID); Tanston® (CL); Templadol® (CL); Tropistan® (ID); Vidan® (RO)

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