INSTRUCTION

for medical use of the medicinal product

 MEFENAMIC ACID

Composition:

Active ingredients: mefenamic acid;

1 capsule contains mefenamic acid 250 mg or 500 mg;

Inactive ingredients:

Capsules 250 mg: talc; lactose monohydrate; corn starch; sodium lauryl sulfate; colloidal silicon dioxide; magnesium stearate;

Capsules 500 mg: talc, stearic acid, corn starch, sodium lauryl sulphate, crospovidone.

Dosage form. Capsules.

Basic physical and chemical properties: hard gelatine capsules size 0 with a light blue cap and yellow light body or vice versa. The capsule contains white or almost white powder.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and anti-rheumatic drugs. Fenamates.

ATC code: М01АG01.

Pharmacological properties.

Pharmacodynamics.

Mefenamic acid is a non-steroidal anti-inflammatory agent (NSAID). It has an anti-inflammatory, analgesic and antipyretic effect. It inhibits the synthesis of inflammatory mediators (prostaglandins, serotonin, kinins), reduces the activity of proteases lysosomes, which are a part of inflammatory reactions. Mefenamic acid affects the phases of exudation and proliferation. It stabilizes protein ultrastructure and cell membranes, reduces permeability of vessels and swelling of tissues. It inhibits cell proliferation in inflammation; increases the resistance of cells and promotes healing. Antipyretic effect is due to inhibition of prostaglandin synthesis and effect on thermoregulation center. Mefenamic acid stimulates the formation of interferon.

Pharmacokinetics.

After oral administration it is rapidly and almost completely absorbed in the intestinal tract. Its maximum concentration in blood is reached in 2-4 hours. The level of concentration in blood is proportional to the dose. In the bloodstream it binds with albumin. The half-life makes 3 hours. It forms a series of metabolites in the liver. 67% of the dose is excreted unchanged in the urine, 20-25% - with faeces.

Clinical particulars.

Indications.

Acute respiratory infections and influenza.

Primary dysmenorrhea. Dysfunctional menorrhagia.

Inflammatory diseases of the musculoskeletal system: rheumatoid arthritis, rheumatism, Bechterew's disease.

Pain syndrome of low and medium intensity: muscular pain, articular pain, traumatic pain, toothache, headache of different etiology, postoperative and postpartum pain.

Contraindications.

Hypersensitivity to mefenamic acid or to any of the excipients. Bronchospasm, angioedema, rhinitis, asthma or urticaria that occurred after use of acetylsalicylic acid or other NSAIDs. Concomitant use of specific COX-2 inhibitors. Present or anamnesis peptic and duodenal ulcers, inflammatory bowel disease, blood diseases, severe heart failure, sever liver or renal dysfunction, gastrointestinal haemorrhages or perforation caused by the intake of nonsteroidal anti-inflammatory drugs, treatment of pain after coronary-artery bypass surgery.

Interaction with other medicinal products and other forms of interaction.

Thiamine, pyridoxine hydrochloride, barbiturates, phenothiazine derivatives, narcotic analgesics, caffeine, diphenhydramine increase the analgesic effect of the drug.

Methotrexate: Concomitant use of mefenamic acid and methotrexate may potentially increase the methotrexate concentrations in plasma and its toxic effect.

Probenecid: decrease in metabolism, delayed excretion of probenecid from the body.

Antihypertensive (ACE inhibitors and angiotensin II receptor antagonists): decrease of antihypertensive effect, increased risk of renal failure especially in elderly patients. Patients should drink enough liquid. It is also necessary to assess renal functions at the beginning of the treatment and during concomitant therapy.

Diuretics: decrease of diuretic effect. Diuretics may increase the nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate a heart failure, reduce a glomerular filtration rate and increase a cardiac glycosides concentration in blood plasma.
Cyclosporine: increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used within 8-12 days after taking mifepristone, because NSAIDs may reduce effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulcers and bleeding.
Antiaggregants and selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding.

Fluoroquinolones: NSAIDs increase the risk of seizures.

Aminoglycosides: NSAIDs increase the risk of nephrotoxic effect.

Tacrolimus: possible risk of nephrotoxicity.

Zidovudine: NSAIDs increase the risk of hematologic toxicity. There is increased risk of bleeding in the joints and hematoma in HIV positive patients with haemophilia who receive concomitant treatment of zidovudine.

Lithium: decrease of lithium excretion and increased risk of lithium toxicity.

Oral anticoagulants: Mefenamic acid increases the activity of oral anticoagulants; therefore their concomitant use increases the risk of hemorrhages. The reduction of the anticoagulant’s dose is possible. Concomitant use of mefenamic acid with oral anticoagulants requires thorough monitoring of prothrombin time. It is unsafe to take NSAIDs with warfarin or heparin. The medical observation is required.

Concomitant use with other NSAIDs increases the anti-inflammatory effects and the likelihood of adverse reactions in the gastrointestinal tract.

Precautions for use.

Mefenamic acid is not used for patients who had hypersensitivity reactions previously (e.g. asthma, bronchospasm, rhinitis, urticaria or angioedema).

Do not use for dehydrated patients who lost fluid as a result of vomiting, diarrhoea or increased urination.

It is necessary to consult a doctor regarding long-term treatment of headaches.

The drug is used with caution in patients with acute presence of cardiovascular disease, hypertension and ischemic heart disease. The use of mefenamic acid may slightly increase the risk of a heart attack or a stroke. Any risk is associated with an increase of dose or long-term treatment. During mefenamic acid treatment, the patients with cardiovascular and cerebrovascular disease should consult a doctor and should not increase the recommended dose or duration of treatment. The drug is used with caution in patients with epilepsy.

Mefenamic acid may cause mild dysfunction of liver and kidneys. For patients who have these disorders, the drug therapy should be discontinued. Patients, treated with mefenamic acid for a long time, should be monitored due to the possibility of liver and renal impairments’ occurrence.

NSAIDs should be used with caution in patients with the history of gastro-intestinal tract diseases (ulcerative colitis, Crohn's disease, inflammatory disease of intestines), due to possible exacerbation. If the use of mefenamic acid leads to gastrointestinal bleeding or perforation, the treatment should be discontinued.

Elderly patients usually have an increased risk of developing gastrointestinal disorders, such as gastrointestinal bleeding and perforation, which may lead to lethal consequences, therefore the treatment should be started from the lowest dosage.

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

Mefenamic acid should be used with caution in patients with high risk of serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. At first manifestations of skin rash, mucous membrane lesions or any signs of increased hypersensitivity, the treatment should be discontinued.

As mefenamic acid may cause blood abnormalities at the long-term use, the monitoring of blood parameters should be carried out. In case of any dyscrasia manifestations the treatment should be discontinued.

Intake of mefenamic acid may cause disorders of gastrointestinal tract (e.g. diarrhoea). These disorders may occur either immediately after the drug intake or after long-term treatment. If such symptoms occur, the drug administration should be discontinued.

The drug should be used with caution in patients who receive concomitant treatment with medicines, which could increase the risk of haemorrhage development, such as corticosteroids, anticoagulants (warfarin) and aspirin.

The use of mefenamic acid may impair female fertility and is not recommended for women attempting to conceive. In case of dysmenorrhoea and menorrhagia symptoms or lack of response, women should consult a doctor.

Mefenamic acid, 250 mg capsule contains lactose, therefore patients with rare hereditary forms of intolerance to galactose, lactase insufficiency or glucosegalactose malabsorption syndrome can not use the drug.

Pregnancy and lactation.

Do not use the drug for pregnant women.

Do not use the drug for breastfeeding women.

Effects on ability to drive and operate machinery.

Be careful when driving or operating mechanisms that require increased attention, because sometimes the drug may cause drowsiness, blurred vision or convulsions.

Routes of administration and dosage.

Oral use.  Take medication after meals.

Intake of 250-500 mg 3-4 times a day is prescribed to adults and children over 12 years. If necessary, the daily dose can be increased to 3 g per day. After a therapeutic effect the daily dose should be reduced to 1 g

The course of treatment for joints diseases can last from 20 days to 2 months or longer. In case of pain syndrome therapy, the course of treatment lasts up to 7 days.

Children.

Recommended for children over 12 years of age.

Overdose.

Symptoms: epigastric pain, nausea, vomiting, drowsiness, headache, rare – diarrhoea, disorientation, agitation, tinnitus, loss of consciousness, and sometimes seizures (mefenamic acid has a tendency to induction of tonic-clonic seizures in overdose). In severe cases – gastrointestinal bleeding, respiratory depression, arterial hypertension, twitching of individual muscle groups, coma. In cases of severe poisoning acute renal failure and liver damage are possible.

Treatment: there is no specific antidote. Gastric lavage with suspension of activated charcoal. Urine alkalization and forced diuresis. Symptomatic therapy. Hemosorbtion and hemodialysis have little effect due to strong binding of mefenamic acid with blood proteins. Kidney and liver functions should be closely monitored. Frequent or prolonged convulsions should be treated with diazepam intravenously.

Adverse reactions.

Gastrointestinal disorders: epigastric pain, anorexia, heartburn, nausea, flatulence, vomiting, enterocolitis, colitis, exacerbation of colitis and Crohn's disease, gastritis, hepatotoxicity, steatorrhea, cholestatic jaundice, hepatitis, pancreatitis, hepatorenal syndrome, haemorrhagic gastritis, peptic ulcer with/or without haemorrhage, melena, ulcerative stomatitis. Gastrointestinal bleeding, dyspepsia, constipation, diarrhoea; perforation or gastrointestinal bleeding, sometimes with fatal consequences, especially in elderly patients. Increased level of liver enzymes in the blood plasma.

Cardiovascular disorders: arterial hypertension, arrhythmia, rarely - congestive heart failure, peripheral edema, syncope, arterial hypotension, palpitations, shortness of breath, thrombotic complications (e.g. myocardial infarction or stroke).

Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnoea.

Renal and urinary disorders: dysuria, cystitis, renal dysfunction, albuminuria, haematuria, oliguria or polyuria, renal failure including papillar necrosis, acute interstitial nephritis, nephrotic syndrome, allergic glomerulonephritis, hyponatremia, hyperkalemia.

Blood system disorders: aplastic anaemia, autoimmune hemolytic anaemia, increased bleeding time, eosinophilia, leukopenia with the risk of infection, sepsis or disseminated intravascular coagulation, thrombocytopenia, reduced haematocrit, thrombocytopenic purpura, agranulocytosis, neutropenia, pancytopenia, bone marrow hypoplasia

Psychiatric and Nervous system disorders: drowsiness or insomnia, fatigue, irritability, agitation, headache, blurred vision, seizures, confusion, depression, hallucinations, optic neuritis, paraesthesia, dizziness, stiff neck, fever, loss of orientation.

Sense organs disorders: tinnitus, ear pain, otalgia, blurred vision, reverse loss of ability to distinguish colors, eye irritation.

Immune system disorders: purpura, hypersensitivity reactions, including skin rash, itching, face edema, allergic rhinitis, angioneurotic edema, laryngeal edema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, urticaria, bullous pemphigus, photosensitivity, asthma, anaphylaxis.

General disorders: glucose intolerance in patients hospitalized with diabetes mellitus, aseptic meningitis, sweating, increased fatigue, malaise, multiple organ failure, pyrexia, positive reaction in some tests on the presence of mefenamic acid and its metabolites in bile and urine.

Storage life. 3 years.

Storage conditions. Store in the original package at temperature not exceeding 30 °С. Keep out of reach of children.

Package. 10 capsules in a blister, 2 blisters in a pack.

Terms of dispensing. Available on a non-prescription basis.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer’s registered address.

E-28, Opp. Fire Brigade, M.I.D.C., Taloja, Dist. Raigad, Maharashtra, IN-410208, India.

Applicant.

Flamingo Pharmaceuticals Ltd.

Applicant’s registered address.

7/1, Corporate Park, Sion-Trombay Road, Chembur, Mumbai - 400071, India