Mefenax

Mefenamic acid is a non-steroidal anti-inflammatory agent with analgesic properties, and a demonstrable antipyretic effect. It has been shown to inhibit prostaglandin activity.

Indications

1. As an anti-inflammatory analgesic for the symptomatic relief of rheumatoid arthritis ( including Still's Disease ), osteoarthritis, and pain including muscular, traumatic and dental pain, headaches of most aetiology, post-operative and post-partum pain; pyrexia in children.

2. Primary dysmenorrhoea.

3. Menorrhagia due to dysfunctional causes and presence of an IUD when other pelvic pathology has been ruled out.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

For oral administration

Adults

2 capsules ( 500mg ) three times daily.

In menorrhagia to be administered on the first day of excessive bleeding and continued according to the judgment of the physician.

In dysmenorrhoea to be administered at the onset of menstrual pain and continued according to the judgment of the physician.

Elderly (Over 65 Years)

As for adults.

Whilst no pharmacokinetic or clinical studies specific to the elderly have been undertaken with Mefenax, it has been used at normal dosage in trials which included many elderly patients.

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy

Mefenax should be used with caution in elderly patients suffering from dehydration and renal disease. Non-oliguric renal failure and proctocolitis have been reported mainly in elderly patients who have not discontinued mefenamic acid after the development of diarrhoea.

Children

It is recommended that children under 12 years of age should be given Mefenamic Acid Suspension (50mg / 5ml).

Mefenax Capsules should be taken preferably with or after food.

Do not exceed the stated dose.

Hypersensitivity to mefenamic acid or any of the other ingredients.

Inflammatory bowel disease

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

Severe heart failure, hepatic failure and renal failure.

Because the potential exists for cross-sensitivity to aspirin, ibuprofen, or other non-steroidal anti-inflammatory drugs, mefenamic acid must not be given to patients who have previously shown hypersensitivity reaction (e.g. asthma, bronchospasm, rhinitis, angioedema or urticaria) to these medicines.

During the last trimester of pregnancy.

Treatment of pain after coronary artery bypass graft (CABG) surgery.

Patients on prolonged therapy should be kept under regular surveillance with particular attention to liver dysfunction, rash, blood dyscrasias or development of diarrhoea.).

Cardiovascular and cerebrovascular effects: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding such as corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as aspirin

When GI bleeding or ulceration occurs in patients receiving mefenamic acid the treatment should be withdrawn.

SLE and mixed connective tissue disease: In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Mefenamic acid should be stopped at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Female fertility: The use of mefenamic acid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of mefenamic acid should be considered.

In dysmenorrhoea and menorrhagia lack of response should alert the physician to investigate other causes.

Epilepsy: Caution should be exercised when treating patients suffering from epilepsy.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

The most frequently reported side effects associated with mefenamic acid involve the gastrointestinal tract.

Diarrhoea occasionally occurs following the use of mefenamic acid. Although this may occur soon after starting treatment, it may also occur after several months of continuous use. The diarrhoea has been investigated in some patients who have continued this drug in spite of its continued presence. These patients were found to have associated proctocolitis. If diarrhoea does develop the drug should be withdrawn immediately and this patient should not receive mefenamic acid again.

Frequencies are not known for the following adverse reactions:

Blood and the lymphatic system disorders

Agranulocytosis, aplastic anaemia, eosinophilia, neutropenia, pancytopenia, thrombocytopenia.

*reversible when mefenamic acid is stopped

Immune system disorders

Metabolism and nutritional disorders

Pyschiatric disorders

Nervous system disorders

Blurred vision, convulsions, insomnia.

Eye disorders

Ear and labyrinth disorders

Cardiac / Vascular disorders

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Palpitations.

Hypotension.

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Elderly or debilitated patients seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population.

Anorexia, colitis, enterocolitis, gastric ulceration with or without haemorrhage, pancreatitis, steatorrhea.

Hepato-bilary disorders

Mild hepatotoxicity, hepatitis, hepatorenal syndrome.

Skin and subcutaneous tissue disorders

Renal and urinary disorders

General disorders

Investigations

A positive reaction in certain tests for bile in the urine of patients receiving mefenamic acid has been demonstrated to be due to the presence of the drug and its metabolites and not to the presence of bile.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

It is important that the recommended dose is not exceeded and the regime adhered to since some reports have involved daily dosages under 3g.

(a) Symptoms

Symptoms include headache, nausea, vomiting epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally convulsions [Mefenamic acid has a tendency to induce tonic-clonic (grand mal) convulsions in overdose]. In cases of significant poisoning acute renal failure and liver damage are possible.

(b) Therapeutic measure

Patients should be treated symptomatically as required

Within one hour of ingestion of a potentially toxic amount activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

Other measures may be indicated by the patient's clinical condition.

Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.

ANIMAL MODELS

Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID) with anti- inflammatory, analgesic and antipyretic properties.

Its anti-inflammatory effect was first established in the UV erythema model of inflammation. Further studies included inhibition of granulation tissue growth into subcutaneous cotton pellets in rats and carrageenin induced rat paw oedema tests.

Antipyretic activity was demonstrated in yeast-induced pyresis in rats. In this model its antipyretic activity was roughly equal to that of phenylbutazone and flufenamic acid, but less than that of indomethacin.

Analgesic activity was demonstrated in tests involving pain sensitivity of rats paws inflamed by brewers yeast. Mefenamic acid was less potent than flufenamic acid in this model.

Prostaglandins are implicated in a number of disease processes including inflammation, modulation of the pain response, dysmenorrhoea, menorrhagia and pyrexia.

In common with most NSAIDs mefenamic acid inhibits the action of prostaglandin synthetase (cyclo oxygenase). This results in a reduction in the rate of prostaglandin synthesis and reduced prostaglandin levels.

The anti-inflammatory activity of NSAIDs in the rat paw oedema test has been correlated with their ability to inhibit prostaglandin synthetase. When mefenamic acid is ranked in both these tests it falls between indomethacin and phenylbutazone and it is probable that inhibition of prostaglandin synthesis contributes to the pharmacological activity and clinical efficacy of mefenamic acid.

There is also considerable evidence that the fenamates inhibit the action of prostaglandins after they have been formed. They therefore both inhibit the synthesis and response to prostaglandins. This double blockade may well be important in their mode of action.

Absorption and Distribution

Mefenamic acid is absorbed from the gastro intestinal tract. Peak levels of 10 mg/l occur two hours after the administration of a 1g oral dose to adults.

Metabolism

Mefenamic acid is predominantly metabolised by cytochrome P450 enzyme CYP2C9 in the liver, first to a 3-hydroxymethyl derivative (metabolite I) and then a 3-carboxyl derivative (metabolite II). Both metabolites undergo secondary conjugation to form glucuronides.

Therefore in patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Elimination

Fifty two percent of a dose is recovered from the urine, 6% as mefenamic acid, 25% as metabolite I and 21% as metabolite II. Assay of stools over a 3 day period accounted for 10-20 % of the dose chiefly as unconjugated metabolite II.

The plasma levels of unconjugated mefenamic acid decline with a half life of approximately two hours.

Preclinical safety data does not add anything of further significance to the prescriber.

None known.

Not applicable.