Mefenamic acid

Concomitant use of mefenamic acid with corticosteroids may increase the risk of gastrointestinal ulceration or bleeding.

The concomitant use of mefenamic acid with selective serotonin reuptake inhibitors (SSRIs) requests caution because of increased risk of gastrointestinal bleeding.

Concomitant consumption of alcohol with mefenamic acid may increase the risk of gastrointestinal bleeding, ulceration and perforation.

Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

Concomitant use of mefenamic acid with sulfonylurea drugs may increase inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.

NSAIDs may enhance the effects of anti-coagulants, such as warfarin. Concurrent administration of mefenamic acid with oral anti-coagulant drugs requires careful prothrombin time monitoring.

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

In concomitant use of mefenamic acid with anti-platelet agents there is increased risk of gastrointestinal ulceration or bleeding.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels.

The concomitant use of mefenamic acid with antihypertensives or diuretics requests caution because a reduction in antihypertensive and diuretic effect has been observed. Diuretics can increase the nephrotoxicity of NSAIDs.

The concomitant use of mefenamic acid with ACE inhibitors, angiotensin-II-receptor antagonists may enhance a reduction in antihypertensive effect and an increased risk of renal impairment especially in elderly patients. Patients should be adequately hydrated and the renal function assessed in the beginning and during concomitant therapy.

The concomitant use of mefenamic acid with aminoglycosides may enhance a reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.

Animal data indicates that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects.

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.

Experimental data implies that mefenamic acid interferes with the anti-platelet effect of low-dose acetylsalicylic acid when given concomitantly, and thus may interfere with acetylsalicylic acid’s prophylactic treatment of cardiovascular disease. However, the limitations of this experimental data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular mefenamic acid use.

Concomitant administration of cholestyramine and mephenamic acid or fluorophenamic acid reduces the rate of absorption of mephenamic acid and fluorophenamic acid from the intestine (Rosenberg & Bates, 1974).

The risk of nephrotoxicity of ciclosporin may be increased with NSAIDs.

Concurrent therapy of mefenamic acid with lithium may enhance a reduction in renal lithium clearance and elevation of plasma lithium levels. Patients should be observed carefully for signs of lithium toxicity.

In concomitant use of mefenamic acid with methotrexate the elimination of the drug can be reduced, resulting in increased plasma levels.

NSAIDs should not be taken for 8-12 days after mifepristone administration, NSAIDs can reduce the effects of mifepristone.

Probenecid causes a reduction in metabolism and elimination of NSAIDs and metabolites.

Possible increased risk of nephrotoxicity when NSAIDS are given with tacrolimus.

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV haemaophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

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). There are insufficient data to exclude such a risk for mefenamic acid.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with mefenamic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

As NSAIDs can interfere with platelet function, they should be used in caution in patients with intracranial haemorrhage and bleeding diathesis.

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

In administration of mefenamic acid, caution should be exercised when treating patients suffering from epilepsy.

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Therefore, mefenamic acid should not be taken by nursing mothers.

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.

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: Haemolytic anaemia*, anaemia, hypoplasia bone marrow, haematocrit decreased, thrombocytopenic purpura, temporary lowering of the white blood cell count (leukopenia) with a risk of infection, sepsis, and disseminated intravascular coagulation.

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

* reversible when mefenamic acid is stopped

Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm, or dyspnoea or (c) assorted skin disorders including rashes of various types, pruritus, urticaria, purpura, angioedema, and more rarely exfoliative or bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Metabolism and nutritional disorders: Glucose intolerance in diabetic patients, hyponatraemia.

Pyschiatric disorders: Confusion, depression, hallucinations, nervousness.

Nervous system disorders: Optic neuritis, headaches, paraesthesia, dizziness, drowsiness, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation. Blurred vision, convulsions, insomnia.

Eye disorders: Eye irritation, reversible loss of colour vision, visual disturbances.

Ear and labyrinth disorders: Ear pain, tinnitus, vertigo.

Cardiac/Vascular disorders: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

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: Asthma, dyspnoea.

Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed.

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: Borderline elevations of one or more liver function tests, cholestatic jaundice. Mild hepatotoxicity, hepatitis, hepatorenal syndrome.

Skin and subcutaneous tissue disorders: Angioedema, laryngeal oedema, erythema multiforme, face oedema, bullous reactions including Lyell’s syndrome (toxic epidermal necrolysis) and Stevens-Johnson syndrome, perspiration, rash, photosensitivity reaction, pruritus and urticaria.

Renal and urinary disorders: Allergic glomerulonephritis, acute interstitial nephritis, dysuria, haematuria, nephrotic syndrome, non-oliguric renal failure (particularly in dehydration), proteinuria, renal failure including renal papillary necrosis.

General disorders: Fatigue, malaise, multi-organ failure, pyrexia.

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.