Mefenamic acid

Mefenamic acid is Non- Steroidal Ant inflammatory Drugs belonging to Analgesic and Anti inflammatory agents.

Mefenamic acid is used in the treatment of Dysmenorrhea, mild to moderate pain. It is also used to treat nonacute abnormal uterine bleeding.

Mefenamic acid is Rapidly absorbed from the gastrointestinal tract and Enters the breast milk (small amounts) with Volume of distribution of 1.06 L/kg.It is Predominantly metabolised in the liver by CYP2C9 isoenzyme into 3-hydroxymethyl mefenamic acid, which may be oxidised further into 3-carboxymefenamic acid; both metabolites undergo secondary conjugation to form glucuronides.

and get excreted Via urine (approx 52%; 6% as unchanged drug, 25% as 3-hydroxymethyl mefenamic acid, 21% as 3-carboxymefenamic acid); faeces (approx 20%, mainly as unconjugated 3-carboxymefenamic acid). Elimination half-life: Approx 2-4 hours.

The onset of action of Mefenamic acid was within 1 hour.

The Tmax of Mefenamic acid was within 2 to 4 hours

Mefenamic acid shows common side effects like diarrhoea, new-onset or worsening of hypertension, hyperkalaemia; renal papillary necrosis and other renal injury (prolonged use); may impair female fertility (prolonged use); aseptic meningitis (particularly in patients with autoimmune disorders), decreased platelet adhesion and aggregation, anaemia.

Mefenamic acid is available in India, Germany, Canada, France, USA

Mefenamic acid, an anthranilic acid derivative, is an NSAID with analgesic and antipyretic properties. It reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes resulting in decreased formation of prostaglandin precursors.

Mefenamic acid is available in the form of Capsules.

Mefenamic acid is used in the treatment of Dysmenorrhea, mild to moderate pain. It is also used to treat nonacute abnormal uterine bleeding.

Mefenamic acid is approved for use in the following clinical indications

Dysmenorrhea, primary: Treatment of primary dysmenorrhea.

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

Although not approved there have been certain off labelled uses documented for Mefenamic acid:

Abnormal uterine bleeding, nonacute

Abnormal uterine bleeding, nonacute (alternative agent) (off-label use): Note: Not indicated for management of acute abnormal bleeding (ie, excessively heavy or prolonged bleeding that requires urgent evaluation). Alternative agent for patients who cannot or choose not to use hormonal therapies .

Oral: 500 mg 3 times daily or 500 mg once followed by 250 mg 4 times daily. Begin at the first sign of menses and continue for 2 to 3 days or until cessation of bleeding; maximum dose: 1.5 g/day.

Dysmenorrhea, primary: Oral: Initial: 500 mg beginning at the onset of bleeding and associated symptoms, followed by 250 mg every 6 hours or 500 mg 3 times daily; usually not to exceed 3 days.

Pain, mild to moderate: Oral: Initial: 500 mg, then 250 mg every 6 hours as needed; usually not to exceed 1 week.

Mefenamic acid is contraindicated in patients with:

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.

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 nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

• Cardiovascular events: 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. 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; consider alternate therapies 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).

• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events: 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. 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; consider alternate therapies 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).

• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; monitor patients with coagulation disorders or who are receiving anticoagulants closely. Anemia may occur; monitor patients on long-term NSAID therapy 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).

Mefenamic acid may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Mefenamic acid is present in breast milk.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered compatible for the treatment of rheumatic and musculoskeletal diseases in lactating patients; agents with a short half-life and established safety data in infants may be preferred .

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Maternal use of NSAIDs should be avoided if the breastfeeding infant has platelet dysfunction, thrombocytopenia, or a ductal-dependent cardiac lesion

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

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). 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 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats and rabbits, there was no evidence of teratogenicity at exposures up to 5 and 10 times the MRHD, respectively. In rat studies with Mefenamic acid, fetotoxicity (postimplantation loss) was observed at exposures 2 times the MRHD, and delayed parturition and an increased incidence of stillbirth were noted at doses equivalent to the MRHD of Mefenamic acid. 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.

Increased risk of gastrointestinal bleeding with excessive alcohol ingestion. May slightly delay the rate, but not the extent of absorption with food.

Common Adverse effects:

diarrhoea, new-onset or worsening of hypertension, hyperkalaemia; renal papillary necrosis and other renal injury (prolonged use); may impair female fertility (prolonged use); aseptic meningitis (particularly in patients with autoimmune disorders), decreased platelet adhesion and aggregation, anaemia.

Less Common Adverse effects:

Nausea, vomiting, dyspepsia, constipation, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of Crohn's disease and colitis, pancreatitis, steatorrhoea, enterocolitis.

Rare Adverse effects

potentially severe blood dyscrasias (e.g. agranulocytosis, thrombocytopenia, aplastic anaemia).

• May increase the risk of bleeding with other NSAIDs or salicylates (e.g. aspirin), anticoagulants (e.g. warfarin), antiplatelet agents, corticosteroids, and SSRIs.
• May enhance the nephrotoxic effect of ciclosporin or tacrolimus.
• May reduce the effects of antihypertensive agents (e.g. ACE inhibitors, angiotensin II antagonists, β-blockers), diuretics (e.g. furosemide, thiazides), and mifepristone (consider avoiding mefenamic acid for at least 8-12 days after mifepristone use).
• May increase the plasma concentration of cardiac glycosides, lithium, aminoglycosides, and methotrexate.
• May prolong the half-life of oral hypoglycaemic agents, increasing the risk of hypoglycaemia. Metabolism and elimination may be reduced with probenecid.
• May increase the risk of haematological toxicity with zidovudine.

The common side effects of Mefenamic acid include the following :

diarrhoea, new-onset or worsening of hypertension, hyperkalaemia; renal papillary necrosis and other renal injury (prolonged use); may impair female fertility (prolonged use); aseptic meningitis (particularly in patients with autoimmune disorders), decreased platelet adhesion and aggregation, anaemia.

Symptoms: Lethargy, drowsiness, headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding. Rarely, diarrhoea, disorientation, excitation, tinnitus, fainting, hypertension, respiratory depression, acute renal failure, and coma; occasionally, convulsions.

Management: Symptomatic and supportive treatment. Induce emesis or perform gastric lavage, then administer activated charcoal. Ensure good urine output. Closely monitor renal and hepatic function. Observe for at least 4 hours following ingestion. In case of frequent or prolonged convulsions, administer IV diazepam.

• Pharmacodynamic

Mefenamic acid is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Mefenamic acid works by reducing hormones that cause inflammation and pain in the body. Mefenamic acid is used to reduce the pain, inflammation, and stiffness caused by rheumatoid arthritis and osteoarthritis.

• Pharmacokinetics

1. https://pubmed.ncbi.nlm.nih.gov/1091001/
2. https://clinicaltrials.gov/ct2/show/NCT01422915
3. https://clinicaltrials.gov/ct2/show/NCT02263547
4. https://www.medicines.org.uk/emc/product/128/smpc.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Mefenamic acid -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Mefenamic acid
5. https://europepmc.org/article/med/6988203