Mefenamic acid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEFENAMIC ACID

Composition:

Active substance: mefenamic acid;

One tablet contains 500 mg of mefenamic acid;

Excipients: microcrystalline cellulose, potato starch, povidone, crospovidone, sodium lauryl sulfate, magnesium stearate, anhydrous colloidal silicon dioxide.

Pharmaceutical form. Tablets.

Main physical and chemical properties: white or greyish-white tablets with a slightly yellowish or greenish tint, oval-shaped, convex on both upper and lower surfaces, with a score line on one side.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Fenamates. ATC code M01A G01.

Pharmacological Properties

Pharmacodynamics

Mefenamic acid is a non-steroidal anti-inflammatory agent. Its anti-inflammatory effect is due to its ability to inhibit the synthesis of inflammatory mediators (prostaglandins, serotonin, kinins, etc.), reduce the activity of lysosomal enzymes involved in the inflammatory response. Mefenamic acid stabilizes cellular protein ultrastructures and membranes, decreases vascular permeability, disrupts oxidative phosphorylation processes, inhibits mucopolysaccharide synthesis, suppresses cell proliferation at the site of inflammation, enhances cellular resistance, and stimulates wound healing. Antipyretic properties are associated with the ability to inhibit prostaglandin synthesis and affect the thermoregulatory center.

Mefenamic acid stimulates interferon production.

In the mechanism of analgesic action, in addition to affecting central pain sensitivity mechanisms, a significant role is played by local action at the inflammatory site and the ability to inhibit the formation of algesic substances (kinins, histamine, serotonin).

Pharmacokinetics

After oral administration, mefenamic acid is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum blood concentration is reached within 2–4 hours after administration. Blood levels are dose-proportional. Steady-state concentration (20 mcg/mL) is achieved by the second day of treatment (1 g four times daily). It is 90% bound to plasma albumins. In the liver, it forms metabolites via oxidation, hydrolysis, and glucuronidation. The elimination half-life (T_1/2) is 2–4 hours. It is excreted from the body unchanged and as metabolites primarily via the kidneys (67% of the dose), and to a lesser extent with feces (20–25%).

Clinical characteristics.

Indications.

Acute viral respiratory infections and influenza.

Mild to moderate pain: muscular, joint, traumatic, dental, headache of various etiologies, postoperative and postpartum pain.

Primary dysmenorrhea. Dysfunctional menorrhagia, including that caused by intrauterine contraceptive devices, in the absence of pelvic organ pathology.

Inflammatory disorders of the musculoskeletal system: rheumatoid arthritis, rheumatism, Bechterew's disease (ankylosing spondylitis).

Contraindications.

Hypersensitivity to the components of the drug.

Due to the risk of cross-sensitivity, mefenamic acid should not be used in patients who have previously experienced hypersensitivity reactions (such as bronchial asthma, bronchospasm, rhinitis, angioedema, or urticaria) following administration of acetylsalicylic acid (aspirin), ibuprofen, or other NSAIDs.

History of gastrointestinal bleeding or perforation associated with previous NSAID therapy.

Active or past history of peptic ulcer/bleeding or recurrent disease (two or more separate confirmed episodes of ulcer or bleeding).

Inflammatory bowel diseases such as Crohn's disease or ulcerative colitis.

Hematopoietic organ disorders.

Severe heart failure (NYHA III-IV).

Severe hepatic impairment (liver cirrhosis and ascites).

Severe renal impairment (creatinine clearance <30 mL/min).

Pain management following coronary artery bypass graft (CABG) surgery (or use of cardiopulmonary bypass apparatus).

Concomitant use of specific COX-2 inhibitors.

Pregnancy or breastfeeding period.

Children under 5 years of age.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of mefenamic acid with other medicinal products that bind to plasma proteins may require dose adjustment.

Thiamine, pyridoxine hydrochloride, barbiturates, phenothiazine derivatives, narcotic analgesics, caffeine, dimedrol: enhanced analgesic effect of the drug.

When mefenamic acid is used concomitantly with methotrexate, the toxic effects of methotrexate are potentiated. NSAIDs, such as mefenamic acid, should be used with caution when administered simultaneously with methotrexate.

Antihypertensive agents, including diuretics, ACE inhibitors, angiotensin II receptor antagonists, and β-blockers: NSAIDs may reduce the effectiveness of diuretics and other antihypertensive agents. In patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced kidney function), concomitant use of cyclooxygenase inhibitors with ACE inhibitors, angiotensin II antagonists, or diuretics may further impair renal function. There is even a risk of acute renal failure, which is usually reversible. Potential interactions should be considered in patients receiving mefenamic acid concomitantly with these antihypertensive drugs. These drugs should be prescribed together cautiously, especially in elderly patients. Patients should receive adequate fluid intake, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter.

Acetylsalicylic acid (aspirin): experimental data indicate that concomitant use of mefenamic acid may inhibit the antiplatelet effect of low-dose aspirin and thus potentially reduce the effectiveness of aspirin in cardiovascular disease prophylaxis. However, due to limitations of these experimental data and uncertainty regarding extrapolation of ex vivo data to clinical situations, definitive conclusions about the impact of regular mefenamic acid use cannot be drawn.

Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides.

Cyclosporine: increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be taken within 8–12 days after mifepristone administration, as NSAIDs may reduce the efficacy of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulcers and bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.

Fluoroquinolones: NSAIDs increase the risk of seizures.

Aminoglycosides: NSAIDs increase the risk of nephrotoxic effects.

Tacrolimus: possible increased risk of nephrotoxic effects.

Zidovudine: NSAIDs increase the risk of hematological toxicity. Increased risk of joint hemorrhage and bruising in HIV-positive hemophilia patients receiving zidovudine therapy.

Lithium preparations: reduced lithium excretion and increased risk of lithium toxicity. Patients receiving mefenamic acid and lithium preparations should be under close medical supervision for early detection of signs of lithium toxicity.

Mefenamic acid enhances the activity of oral anticoagulants, thus increasing the risk of bleeding when used concomitantly. Concomitant use of mefenamic acid with oral anticoagulants requires careful monitoring of prothrombin time. NSAIDs should be used with warfarin or heparin only with special caution and under mandatory medical supervision. This applies both to anticoagulants such as warfarin and to newer anticoagulants such as apixaban, dabigatran, and rivaroxaban.

Oral hypoglycemic agents: inhibition of sulfonylurea drug metabolism, prolonged elimination half-life, and increased risk of hypoglycemia.

There have been reports that NSAIDs affect the action of oral antidiabetic drugs. Therefore, mefenamic acid should be used with caution when administered concomitantly with oral antidiabetic agents or insulin.

Concomitant use with other NSAIDs increases anti-inflammatory effect and the likelihood of gastrointestinal adverse events.

Special precautions for use.

Adverse reactions to mefenamic acid can be minimized by using the lowest effective dose for the shortest possible duration.

Patients undergoing prolonged treatment with mefenamic acid should be under continuous medical supervision for the development of hepatic dysfunction, skin rashes, blood dyscrasias, or diarrhea. If any of these pathological conditions or symptoms occur, treatment should be discontinued immediately.

Prolonged use of the drug for headache treatment may lead to worsening of headache. In such cases, treatment should be discontinued and medical advice sought.

Mefenamic acid should be used with caution in patients who are dehydrated due to vomiting, diarrhea, or increased diuresis, and in patients with renal impairment, especially elderly patients. Cases of non-oliguric renal failure and proctocolitis have been reported, primarily in elderly patients who continued mefenamic acid treatment after the onset of diarrhea.

The drug should be prescribed cautiously to patients with epilepsy.

Mefenamic acid should be used with caution in patients with bronchial asthma (including in medical history), as NSAIDs have been reported to trigger bronchospasm in such patients.

Use of NSAIDs may cause dose-dependent reduction in prostaglandin synthesis and provoke the development of renal failure. Patients at highest risk include those with impaired renal, hepatic, or cardiac function, patients taking diuretics, and elderly patients. Renal function should be monitored in such patients.

Caution is also required when administering the drug to patients concurrently taking ACE inhibitors or those at increased risk of hypovolemia. In rare cases, NSAIDs, including mefenamic acid, may cause interstitial nephritis, glomerulitis, papillary necrosis, and nephrotic syndrome. NSAIDs inhibit the synthesis of renal prostaglandins, which play a role in maintaining renal perfusion in patients with impaired renal circulation and blood volume. In these patients, NSAID use may provoke overt renal failure, which usually returns to baseline after discontinuation of the drug. Patients with heart failure, liver failure, nephrotic syndrome, or evident kidney disease are particularly susceptible to this reaction. These patients should be closely monitored during NSAID therapy.

Mild disturbances in liver and kidney function may occur during treatment with mefenamic acid. If such disturbances develop, the drug should be discontinued. Patients receiving long-term mefenamic acid therapy should be under medical supervision due to the potential for liver and kidney function disturbances.

There are no special recommendations for drug use in cases of mild impairment of liver or kidney function.

The drug should be prescribed with caution to patients with acute cardiovascular failure, arterial hypertension, or ischemic heart disease.

Clinical trial data and epidemiological evidence suggest that the use of certain NSAIDs (particularly at high doses and over prolonged periods) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There is insufficient data to exclude such a risk with mefenamic acid.

If mefenamic acid is required in patients with cardiovascular or cerebrovascular diseases, medical consultation is advised. During treatment, the recommended dose or duration should not be exceeded. Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate evaluation and medical advice, as fluid retention and edema have been reported with NSAID use. Long-term treatment with mefenamic acid in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes mellitus, or smoking) should be initiated by a physician after careful benefit-risk assessment.

The relative increase in cardiovascular risk appears to be similar in patients with or without pre-existing cardiovascular disease or risk factors. However, in absolute terms, patients with existing cardiovascular disease or risk factors are likely to have a higher risk due to their higher baseline incidence.

Mefenamic acid should be used with caution in patients with intracranial hemorrhage or hemorrhagic diathesis due to the ability of NSAIDs to inhibit platelet function.

Mefenamic acid may cause gastrointestinal disorders (e.g., diarrhea), which may occur immediately after drug administration or after prolonged use. If such symptoms occur, the drug should be discontinued.

There have been reports of potentially fatal gastrointestinal bleeding, ulcers, or perforations occurring at any stage of NSAID treatment, regardless of prior warning symptoms or history of severe gastrointestinal disorders. Smoking and alcohol consumption are additional risk factors.

NSAIDs should be used with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn’s disease), as disease exacerbation may occur. If mefenamic acid causes gastrointestinal bleeding or perforation, treatment should be discontinued.

Elderly patients generally have an increased risk of gastrointestinal adverse effects, particularly gastrointestinal bleeding and perforation, which may be fatal; therefore, treatment should be initiated at the lowest dose.

Patients at risk of gastrointestinal bleeding, such as elderly patients or those concurrently taking low-dose acetylsalicylic acid (aspirin) or other drugs that may increase gastrointestinal risk, should consult a physician regarding the possibility of combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors).

Concomitant use of mefenamic acid with other systemic NSAIDs (including COX-2 inhibitors) should be avoided (see section "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Mefenamic acid should be used with caution in patients concurrently taking drugs that may increase the risk of ulceration or bleeding, such as corticosteroids, anticoagulants (including warfarin), SSRIs, or antiplatelet agents (including acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

Patients with systemic lupus erythematosus or mixed connective tissue diseases have an increased risk of aseptic meningitis.

Mefenamic acid should be prescribed cautiously to patients at high risk of serious skin reactions. Serious skin reactions, some of which were fatal, including exfoliative dermatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been very rarely observed during NSAID treatment (see section "Adverse reactions"). The risk of such reactions is likely highest at the beginning of treatment, as most cases occurred within the first month. Mefenamic acid should be discontinued at the first sign of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Like other NSAIDs, mefenamic acid inhibits platelet aggregation and thereby prolongs bleeding time; this should be considered when assessing bleeding time. Patients with coagulation disorders should be carefully monitored. During long-term treatment, blood parameters and renal function should be monitored, as mefenamic acid may cause pathological changes in blood. This is particularly important in patients with pre-existing renal impairment and elderly patients. If any signs of dyscrasia occur, treatment should be discontinued.

Limited data suggest that drugs inhibiting cyclooxygenase/prostaglandin synthesis may impair female fertility by affecting ovulation. This effect is reversible after discontinuation of treatment. Mefenamic acid may impair female fertility and is not recommended for women attempting to conceive. If used in women for symptoms of dysmenorrhea or menorrhagia without therapeutic effect, medical advice should be sought.

Mefenamic acid should be used with caution in patients with slow metabolism mediated by CYP2C9, as well as in patients expected to have slow CYP2C9 metabolism based on the metabolism of other CYP2C9 substrates, due to the possibility of abnormally high plasma levels of mefenamic acid resulting from reduced metabolic clearance.

Important information about excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

The drug is not administered to women during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonic/fetal development. Administration of prostaglandin synthesis inhibitors to animals has been shown to increase pre- and post-implantation losses and embryofetal mortality. In addition, increased incidence of various developmental abnormalities, including cardiovascular malformations, has been observed in animals treated with prostaglandin synthesis inhibitors during organogenesis. According to epidemiological studies, use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of spontaneous abortion, congenital heart defects, and gastroschisis. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%.

From the 20th week of pregnancy, use of non-steroidal anti-inflammatory drugs may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after initiation of treatment and is usually reversible after discontinuation of the drug. Additionally, there have been reports of fetal ductus arteriosus constriction after NSAID treatment in the second trimester, which in most cases resolved after stopping treatment.

Use of any prostaglandin synthesis inhibitor during the third trimester of pregnancy may cause:

In the fetus:

• Development of cardiopulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

• Renal dysfunction, which may progress to renal failure with development of oligohydramnios (see above);

In the mother and newborn, as well as at the end of pregnancy:

• Prolonged bleeding time, antiplatelet effect, which may occur even with low-dose drug use;

• Inhibition of uterine contractility, leading to delayed onset of labor or prolonged labor.

Breastfeeding

Due to the passage of mefenamic acid into breast milk and the associated potential adverse effects on the infant, the drug is contraindicated during breastfeeding.

Fertility

Use of mefenamic acid may impair female fertility and is therefore not recommended for women attempting to conceive. Consideration should be given to discontinuing mefenamic acid in women experiencing difficulties with conception or undergoing infertility evaluation.

Ability to affect reaction speed when driving or operating machinery

Caution should be exercised when driving or operating machinery requiring high attention, as the drug may occasionally cause drowsiness, fatigue, blurred vision, or seizures.

Dosage and Administration

The medicinal product should be used under the supervision of a physician who determines the dose and duration of treatment. Administer orally. The medicinal product should be taken after food.

Adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

For adults and children aged 12 years and older, the recommended dose is 250–500 mg 3–4 times daily. If clinically indicated and well tolerated, the daily dose may be increased up to the maximum of 3000 mg. After achieving the therapeutic effect, the dose should be reduced to 1000 mg/day.

For children aged 5 to 12 years: 250 mg 3–4 times daily.

The treatment course for joint diseases may last from 20 days to 2 months or longer. For pain management, the treatment course lasts up to 7 days.

Children

The medicinal product is contraindicated in children under 5 years of age.

Overdose

Symptoms: epigastric pain, nausea, vomiting, drowsiness, headache, rarely – diarrhea, disorientation, excitement, tinnitus, dizziness, loss of consciousness, hallucinations, and occasionally seizures (mefenamic acid has a tendency to induce tonic-clonic seizures in overdose). In severe cases – gastrointestinal bleeding, respiratory depression, arterial hypertension, muscle twitching, coma. In cases of significant poisoning, renal and hepatic failure may occur. Fatal outcomes are possible.

Treatment: There is no specific antidote. Symptomatic treatment should be administered as needed. Activated charcoal may be useful if administered within 1 hour after ingestion of an excessive dose of mefenamic acid. For adult patients, gastric lavage may be considered within 1 hour after ingestion of a potentially life-threatening dose of mefenamic acid. Adequate diuresis and urinary alkalinization should be ensured. Renal and hepatic functions should be closely monitored. The patient should be observed for at least 4 hours after ingestion of a potentially toxic dose of mefenamic acid. Frequent or prolonged seizures should be controlled by intravenous administration of diazepam. Other measures may be implemented depending on the patient's clinical condition. Hemoperfusion and hemodialysis are poorly effective due to the strong binding of mefenamic acid and its metabolites to plasma proteins.

Adverse Reactions

The most common adverse reactions associated with the use of mefenamic acid are gastrointestinal disorders. Diarrhea may occur both during the first days of treatment and after several months of continuous use. In patients who continued taking mefenamic acid after the onset of diarrhea, cases of proctocolitis have been reported. If diarrhea develops, mefenamic acid must be discontinued immediately. In such cases, the drug should not be used again.

Eye disorders: Visual disturbances (blurred vision), reversible color vision impairment, eye irritation.

Ear and labyrinth disorders: Tinnitus, otalgia, vertigo.

Respiratory, thoracic and mediastinal disorders: Bronchial asthma, dyspnea, bronchospasm.

Gastrointestinal disorders: Epigastric pain, abdominal pain, hematemesis, anorexia, heartburn, nausea, flatulence, vomiting, enterocolitis, colitis, exacerbation of colitis and Crohn’s disease, gastritis, hepatotoxicity, liver function abnormalities, steatorrhea, cholestatic jaundice, hepatitis, pancreatitis, hepatorenal syndrome, hemorrhagic gastritis, peptic ulcer with or without bleeding, melena, ulcerative stomatitis. Gastrointestinal bleeding or perforation, sometimes fatal, particularly in elderly patients, dyspepsia, constipation, diarrhea.

Renal and urinary disorders: Dysuria, cystitis. Renal function impairment, sodium and fluid retention, albuminuria, hematuria, oliguria or polyuria, renal failure including papillary necrosis, acute interstitial nephritis, nephrotic syndrome, allergic glomerulonephritis, proteinuria, non-oliguric renal failure (especially in cases of dehydration).

Metabolism and nutrition disorders: Impaired glucose tolerance in patients with diabetes mellitus, hyponatremia, hyperkalemia.

Nervous system disorders: Drowsiness or insomnia, weakness, fatigue, irritability, excitation, headache, blurred vision, convulsions, optic neuritis, paresthesia, dizziness, fever, disorientation; aseptic meningitis (particularly in patients with autoimmune disorders such as systemic lupus erythematosus or mixed connective tissue disease), with symptoms such as nuchal rigidity, headache, nausea, vomiting.

Psychiatric disorders: Nervousness, confusion, depression, hallucinations.

Cardiac disorders: Arterial hypertension, arrhythmia, palpitations, rarely congestive heart failure, peripheral edema, syncope, arterial hypotension, tachycardia, dyspnea, thrombotic complications (e.g., myocardial infarction or stroke).

Blood and lymphatic system disorders: Aplastic anemia, autoimmune hemolytic anemia, prolonged bleeding time, eosinophilia, leukopenia with risk of infection, sepsis or disseminated intravascular coagulation, thrombocytopenia, decreased hematocrit, thrombocytopenic purpura, agranulocytosis, neutropenia, pancytopenia, bone marrow hypoplasia.

Immune system disorders: Allergic rhinitis, hypersensitivity reactions (reported in association with NSAID use), which may include: non-specific allergic reactions and anaphylaxis, respiratory tract reactivity including asthma, asthma exacerbation, bronchospasm and dyspnea, or various skin reactions including rash, urticaria, pruritus, purpura, angioedema, and less commonly exfoliative and bullous dermatoses (including toxic epidermal necrolysis, erythema multiforme).

Skin and subcutaneous tissue disorders: Angioedema, laryngeal edema, facial edema, skin rash, pruritus, erythema multiforme, urticaria, bullous reactions including toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); increased sweating, bullous pemphigoid, photosensitivity.

Laboratory findings: Positive tests for mefenamic acid and its metabolites in bile and urine. Increased plasma liver enzymes.

Other: Multiorgan failure, hypothermia (in children).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per blister, 1, 2 or 10 blisters per carton.

Supply category.

Over-the-counter: tablets № 10 (10 × 1), № 20 (10 × 2).

By prescription only: tablets № 100 (10 × 10).

Manufacturer: JSC "Lubnipharm".

Manufacturer's address and location of manufacturing activity:

16 Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.