Pharmacological properties
Pharmacodynamics. Mefenamic acid - NSAID, has anti-inflammatory, analgesic and antipyretic effects. Prostaglandins are involved in a number of pathological processes, including inflammation, modulation of the pain response, dysmenorrhea, menorrhagia and hyperthermia. Like most NSAIDs, mefenamic acid inhibits prostaglandin synthetase (COX), which leads to a slowdown in the synthesis of prostaglandins and a decrease in their levels. There is evidence that fenamates inhibit the action of already synthesized prostaglandins. Mefenamic acid is able to inhibit the synthesis of other inflammatory mediators (serotonin, kinins, etc.), reduce the activity of lysosomal enzymes involved in the inflammatory reaction. Mefenamic acid stabilizes protein ultrastructures and cell membranes, reduces vascular permeability, inhibits the synthesis of mucopolysaccharides, inhibits cell proliferation in the focus of inflammation, increases cell resistance and stimulates wound healing. In the mechanism of analgesic action, a significant role is played by the local effect of mefenamic acid on the focus of inflammation and its ability to inhibit the formation of algogens (kinins, histamine, serotonin) along with the effect on the central mechanisms of pain sensitivity. Antipyretic properties are associated with the ability to inhibit the synthesis of prostaglandins and affect the thermoregulation center. Mefenamic acid stimulates the formation of interferon.
Pharmacokinetics
Absorption and distribution. After oral administration, mefenamic acid is rapidly and fairly completely absorbed from the gastrointestinal tract. C max in the blood is reached 2-4 hours after oral administration. The concentration level in the blood is proportional to the dose. In adults, a peak level of 10 mg/l is reached 2 hours after oral administration of mefenamic acid at a dose of 1000 mg. Binding to blood albumin is 90%.
Metabolism: Mefenamic acid is metabolized by the cytochrome P450 enzyme CYP 2C9 in the liver, first to the 3-hydroxymethyl derivative (metabolite I) and then to the 3-carboxyl derivative (metabolite II). Both metabolites undergo secondary conjugation to form glucuronides. Mefenamic acid should be used with caution in patients who are poor metabolizers of CYP 2C9, as well as in patients who are expected to be poor metabolizers of CYP 2C9, taking into account the metabolism of other CYP 2C9 substrates, since abnormally high plasma levels of mefenamic acid may occur in such patients due to reduced metabolic clearance.
Excretion. 52% of the administered dose of mefenamic acid is excreted in the urine (6% unchanged, 25% as metabolite I, 21% as metabolite II). In the analysis of feces over a 3-day period, 10-20% of the dose was detected, mainly as unconjugated metabolite II. T ½ is 2-4 hours.
Indication
Acute respiratory viral infections and influenza.
Low and medium intensity pain: muscular, joint, traumatic, dental, headache of various etiologies, postoperative and postpartum pain.
Primary dysmenorrhea. Dysfunctional menorrhagia, including that caused by the presence of intrauterine contraceptives, in the absence of pathology of the pelvic organs.
Inflammatory diseases of the musculoskeletal system: rheumatoid arthritis, rheumatism, Bechterew's disease.
Application
The drug should be used under the supervision of a doctor who determines the dose and duration of treatment. Side effects of mefenamic acid can be minimized by using the minimum effective dose of the drug for a short period.
The drug is intended for oral use. The drug should be taken during or after meals.
Adults and children over 12 years of age. 250-500 mg 3-4 times a day.
According to indications and with good tolerability, the dose can be increased to a maximum of 3000 mg. After achieving a therapeutic effect, the dose should be reduced to 1000 mg/day.
Children aged 5 to 12 years. 250 mg 3-4 times a day.
Elderly patients (65 years and older): No dose adjustment is required (see Precautions).
Do not exceed the recommended dose.
When treating pain syndrome, the course of treatment lasts up to 7 days.
For dysmenorrhea, the drug should be used from the first day of menstrual pain. The duration of use of the drug is determined by the doctor.
In case of menorrhagia, the drug should be used from the first day of heavy bleeding. The duration of use of the drug is determined by the doctor.
The course of treatment for joint diseases can last from 20 days to 2 months or more.
Contraindication
Hypersensitivity to mefenamic acid or any other component of the drug.
Due to the risk of cross-sensitivity, mefenamic acid should not be used in patients who have previously experienced hypersensitivity reactions (e.g. asthma, bronchospasm, rhinitis, angioedema or urticaria) after taking acetylsalicylic acid/aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs.
Inflammatory bowel diseases.
History of gastrointestinal bleeding or perforation associated with previous NSAID therapy.
History of active or recurrent peptic ulcer/bleeding (two or more separate confirmed episodes of ulceration or bleeding).
Severe heart failure (see Precautions).
Diseases of the blood-forming organs.
Severe hepatic or renal insufficiency (see Precautions).
Concomitant use of specific COX-2 inhibitors.
Galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
Pregnancy and breastfeeding.
Age up to 5 years.
Side effects
When using mefenamic acid, frequent side effects are gastrointestinal disorders. Diarrhea may occur both during the first days of using mefenamic acid and after several months of continuous use. Cases of proctocolitis have been reported in patients who did not stop using mefenamic acid after diarrhea. In case of diarrhea, mefenamic acid should be stopped immediately. In this case, this drug should be used again.
Mental disorders: confusion, depression, hallucinations, nervousness, weakness, irritability, agitation.
Nervous system: headache, dizziness, drowsiness, insomnia, optic neuritis, blurred vision, paresthesias, convulsions, aseptic meningitis (especially in patients with existing autoimmune disorders such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as occipital muscle rigidity, headache, nausea, vomiting, fever, disorientation (see Special warnings and precautions for use).
On the part of the organ of vision: eye irritation, reversible loss of color vision, visual impairment.
On the part of the organ of hearing: earache, tinnitus, vertigo.
Cardiovascular system: edema, hypertension, heart failure (registered in connection with taking NSAIDs), arrhythmia, palpitations, hypotension, syncope.
Clinical trial data and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and over long periods) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see Precautions).
From the blood and lymphatic system: anemia (including hemolytic anemia, aplastic anemia reversible after discontinuation of mefenamic acid), bone marrow hypoplasia, decreased hematocrit, transient leukopenia with the risk of infection, sepsis; increased bleeding time, thrombocytopenic purpura, DIC, thrombocytopenia, agranulocytosis, eosinophilia, neutropenia, pancytopenia.
From the respiratory system: asthma, shortness of breath, bronchospasm.
On the part of the digestive system: gastrointestinal ulceration, perforation or gastrointestinal bleeding, sometimes fatal, especially in elderly patients (see Features of use); anorexia, nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, epigastric pain, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease, gastritis, hemorrhagic gastritis, colitis, enterocolitis, peptic ulcer with or without bleeding, pancreatitis, steatorrhea.
On the part of the hepatobiliary system: marginal increase in the activity of liver enzymes in the blood plasma, cholestatic jaundice, moderate hepatotoxicity, hepatitis, hepatorenal syndrome.
Metabolic disorders: impaired glucose tolerance in patients with diabetes mellitus, hyponatremia, hyperkalemia.
From the urinary system: renal dysfunction, dysuria, hematuria, cystitis, oliguria or polyuria, proteinuria, allergic glomerulonephritis, acute interstitial nephritis, nephrotic syndrome, non-oliguric renal failure (especially with dehydration), renal failure, including renal papillary necrosis.
Skin and subcutaneous tissue disorders: angioedema, laryngeal edema, facial edema, erythema multiforme, bullous reactions including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, increased sweating, rash, photosensitivity, pruritus, urticaria.
On the part of the immune system: allergic rhinitis, hypersensitivity reactions (registered in connection with the use of NSAIDs), which may include: non-specific allergic reactions and anaphylaxis, airway reactivity, including asthma, exacerbation of asthma, bronchospasm and dyspnea, or various forms of skin reactions, including rash of various types, itching, urticaria, purpura, angioedema, and less often - exfoliative and bullous dermatosis, including toxic epidermal necrolysis, erythema multiforme.
General disorders: fatigue, malaise, multiorgan failure, pyrexia.
Laboratory tests: A positive reaction for the presence of bile pigments in the urine in patients taking mefenamic acid may be due to taking the drug.
Special instructions
Side effects of mefenamic acid can be minimized by using the lowest effective dose for the shortest period of time.
During long-term treatment with mefenamic acid, patients should be monitored for the development of liver dysfunction, rash, blood dyscrasias, or diarrhea. If any of these pathological conditions or symptoms develop, treatment should be discontinued immediately (see Adverse Reactions).
Mefenamic acid should be used with caution in patients dehydrated by vomiting, diarrhea, or increased diuresis, in patients with renal insufficiency, and especially in elderly patients.
Taking mefenamic acid may cause gastrointestinal disturbances (e.g. diarrhoea). These may occur either immediately after taking the drug or after prolonged use. If such symptoms occur, the drug should be discontinued.
NSAIDs should be taken with caution in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease, inflammatory bowel disease), as exacerbation of the disease is possible.
Elderly patients. Elderly patients have an increased frequency of adverse reactions associated with the use of nonsteroidal anti-inflammatory drugs, especially gastrointestinal bleeding and perforation, which can be fatal. The drug should be used in the lowest effective dose for the shortest possible period. During NSAID therapy, it is necessary to monitor the condition of the gastrointestinal tract for possible disorders, especially gastrointestinal bleeding. Mefenamic acid should be used with caution in elderly patients with dehydration and renal disease. Cases of nonoliguric renal failure and proctocolitis have been reported, mainly in elderly patients who did not stop taking mefenamic acid after the onset of diarrhea.
Respiratory system: Mefenamic acid should be used with caution in patients with bronchial asthma (including a history of it), as NSAIDs have been reported to accelerate the development of bronchospasm in such patients.
Cardiovascular failure, impaired liver and kidney function. The use of nonsteroidal anti-inflammatory drugs can lead to a dose-dependent decrease in prostaglandin synthesis and provoke the development of renal failure. The highest risk of developing this reaction is observed in patients with impaired renal function, liver, heart failure, patients taking diuretics, and elderly patients. In such patients, renal function should be monitored (see Side effects, Interactions).
When using mefenamic acid, moderate violations of liver and kidney function are possible. Patients who develop such violations should stop taking the drug. Patients who use mefenamic acid for a long time should be under the supervision of a doctor due to the possibility of developing violations of liver and kidney function.
Cardiovascular and cerebrovascular effects: Clinical trial data and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and over long periods) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). There is insufficient evidence to exclude such a risk with mefenamic acid.
If necessary, the use of mefenamic acid in patients with cardiovascular and cerebrovascular diseases should consult a doctor. During treatment, the recommended dose should not be increased or the duration of treatment should be increased. In patients with uncontrolled arterial hypertension, congestive heart failure diagnosed with coronary artery disease, peripheral arterial disease and / or cerebrovascular disease, treatment with mefenamic acid can be prescribed by a doctor only after a careful analysis of the benefit / risk ratio. For patients with a history of hypertension and / or mild to moderate congestive heart failure, an appropriate examination and advice from a doctor are necessary, since cases of fluid retention and edema have been reported in connection with the use of non-steroidal anti-inflammatory drugs. For patients with risk factors for cardiovascular complications (such as hypertension, hyperlipidemia, diabetes mellitus, smoking), long-term treatment with mefenamic acid may be prescribed by a doctor after a careful analysis of the benefit/risk ratio.
Mefenamic acid should be used with caution in patients with intracranial hemorrhage and hemorrhagic diathesis due to the ability of NSAIDs to suppress platelet function.
Gastrointestinal bleeding, ulceration and perforation. Cases of potentially fatal gastrointestinal bleeding, ulceration or perforation have been reported at any time during treatment with NSAIDs, regardless of the presence of warning symptoms or a history of serious gastrointestinal disorders. Smoking and alcohol consumption are additional risk factors.
The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing NSAID dose, with a history of ulceration, especially complicated by bleeding or perforation (see Adverse Reactions), and in elderly patients. Patients at risk of gastrointestinal bleeding, such as the elderly, and patients taking concomitant low-dose acetylsalicylic acid or other drugs that may increase the risk for the gastrointestinal tract, should consult a doctor about the possibility of using combination therapy with protective drugs (e.g. misoprostol or proton pump inhibitors).
Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment.
If gastrointestinal bleeding or ulceration occurs in patients taking mefenamic acid, treatment should be discontinued.
Systemic lupus erythematosus and mixed connective tissue disease: Patients with systemic lupus erythematosus and mixed connective tissue disease may be at increased risk of aseptic meningitis (see Adverse Reactions).
Effects on the skin and subcutaneous tissue. Severe skin reactions, which may be fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The risk of such reactions is greatest early in therapy, with the majority of cases occurring within the first month of treatment. At the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity, mefenamic acid should be discontinued.
Effects on female fertility. There is limited evidence that drugs that inhibit cyclooxygenase/prostaglandin synthesis may reduce female fertility by affecting ovulation. This process is reversible after discontinuation of treatment. Mefenamic acid is not recommended for use in women who are attempting to conceive; in women who have difficulty conceiving or are undergoing investigation for infertility.
In the absence of a therapeutic effect when using mefenamic acid for dysmenorrhea and menorrhagia, you should consult a doctor.
Epilepsy: Mefenamic acid preparations should be used with caution in patients with epilepsy.
Metabolism by CYP 2C9: Mefenamic acid should be used with caution in patients who are poor metabolizers of CYP 2C9, as well as in patients who are expected to be poor metabolizers of CYP 2C9, taking into account the metabolism of other CYP 2C9 substrates, since such patients may have abnormally high plasma levels of mefenamic acid due to reduced metabolic clearance (see Pharmacological Properties).
Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy and breastfeeding. The drug is not used in women during pregnancy and breastfeeding.
Children. The drug is contraindicated in children under 5 years of age.
Ability to influence the reaction rate when driving or operating other mechanisms. Caution should be exercised when driving or operating other mechanisms that require increased attention, as sometimes the use of the drug can cause dizziness, drowsiness, increased fatigue, visual impairment, and seizures.
Interactions
Concomitant use of mefenamic acid with other drugs that bind to plasma proteins may require dose adjustment.
Other analgesics, including selective COX-2 inhibitors. The simultaneous use of two or more NSAIDs (including acetylsalicylic acid) should be avoided, as this may lead to an increased risk of side effects.
Antiplatelet agents, corticosteroids. Increased risk of gastrointestinal bleeding or ulcers (see Precautions).
Acetylsalicylic acid. Experimental data suggest that mefenamic acid, when used concomitantly, may inhibit the antiplatelet effect of low-dose acetylsalicylic acid and, therefore, may reduce the effectiveness of preventive cardiovascular treatment with acetylsalicylic acid. However, due to the limitations of these experimental data and the uncertainty regarding the extrapolation of ex vivo data to the clinical situation, no clear conclusions can be drawn regarding the effects of mefenamic acid when used regularly.
Lithium: Decreased renal clearance of lithium and increased plasma lithium levels. Patients taking mefenamic acid and lithium should be monitored closely for signs of lithium toxicity.
Antihypertensives and diuretics. There is a decrease in the hypotensive and diuretic effects. Diuretics may increase the nephrotoxicity of NSAIDs.
ACE inhibitors and angiotensin II receptor antagonists. Reduced hypotensive effect and increased risk of renal dysfunction, especially in elderly patients. In such patients, renal function should be monitored at the beginning and during concomitant therapy. Patients should drink sufficient fluids.
Aminoglycosides: Decreased renal function in patients at increased risk of renal impairment, decreased elimination of aminoglycosides and increased plasma concentrations.
Cardiac glycosides: NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides.
Cyclosporine: The risk of nephrotoxicity of cyclosporine may be increased when used concomitantly with nonsteroidal anti-inflammatory drugs.
Oral hypoglycemic agents. Inhibition of the metabolism of sulfonylurea drugs, prolongation of T ½ and increased risk of hypoglycemia.
Methotrexate: The elimination of methotrexate may be reduced, leading to increased plasma levels and increased toxic effects.
Mifepristone. NSAIDs should not be taken for 8-12 days after taking mifepristone, nonsteroidal anti-inflammatory drugs may reduce its therapeutic effect.
Quinolone antibiotics: Animal studies suggest that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may be at increased risk of seizures.
Zidovudine: There is an increased risk of hematological toxicity when zidovudine is used concomitantly with NSAIDs. There is evidence of an increased risk of hemarthrosis and hematoma in HIV-infected hemophiliacs when zidovudine is combined with ibuprofen.
Tacrolimus: Possible increased risk of nephrotoxic effects.
Antidepressants (selective serotonin reuptake inhibitors). Increased risk of gastrointestinal bleeding (see Precautions).
Probenecid: Decreased metabolism and elimination of NSAIDs and their metabolites.
Thiamine, pyridoxine hydrochloride, barbiturates, phenothiazine derivatives, narcotic analgesics, caffeine, diphenhydramine enhance the analgesic effect of mefenamic acid.
Overdose
Symptoms: epigastric pain, nausea, vomiting, drowsiness, headache, rarely diarrhea, disorientation, agitation, tinnitus, loss of consciousness, sometimes convulsions (mefenamic acid can induce tonic-clonic convulsions in case of overdose). In severe cases - gastrointestinal bleeding, respiratory depression, ag, twitching of individual muscle groups, coma. In case of significant poisoning, acute respiratory failure and liver damage are possible.
Treatment: symptomatic therapy. There is no specific antidote. The use of activated charcoal is advisable if more than 1 hour has passed after taking an excessive dose of mefenamic acid. As an alternative, gastric lavage should be considered in adults within 1 hour after taking a potentially life-threatening dose of mefenamic acid. Forced diuresis and alkalinization of urine should be ensured. Kidney and liver function should be carefully monitored. The patient's condition should be observed for at least 4 hours after taking a potentially toxic dose of mefenamic acid. Frequent or prolonged seizures should be treated with intravenous diazepam. Other measures may be prescribed depending on the clinical condition of the patient. Hemosorption and hemodialysis are ineffective due to the strong binding of mefenamic acid and its metabolites to blood plasma proteins.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
