Source: Υπουργείο Υγείας (CY) Revision Year: 2018 Publisher: Remedica Ltd, Aharnon Street, Limassol Industrial Estate, 3056 Limassol, Cyprus
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, Posology and method of administration, and G.I and cardiovascular risks below).
Patients on prolonged therapy should be kept under regular surveillance with particular attention to liver dysfunction, rash, blood dyscrasias or development of diarrhoea. Appearance of any of these symptoms should be regarded as an indication to discontinue therapy immediately.
Precaution should be taken in patients suffering from dehydration and renal disease, particularly the elderly.
Prolonged use of NSAIDs in the elderly is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.
Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of ‘Medication Overuse Headache’ should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with use of NSAIDs (see section, 4.8 Undesirable effects). 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. Alfoxan hard capsules should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
In patients with Systemic Lupus Erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8, Undesirable effects).
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 trials 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).
Caution is required in patients with history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2, Posology and method of administration).
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events. Smoking and alcohol use are added risk factors.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3, Contraindications), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5, Interaction with other medicinal products and other forms of interaction).
Patients with a history of GI toxicity, particularly when elderly, should report any abdominal symptoms (especially GI bleeding) particularly in the initial stages.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or anti-platelet agents such as aspirin (see section 4.5, Interaction with other medicinal products and other forms of interaction).
When GI bleeding or ulceration occurs in patients receiving Alfoxan hard capsules, the treatment should be withdrawn.
As NSAIDs can interfere with platelet function, they should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.
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.
Caution should be exercised when treating patients suffering from epilepsy.
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 (see section 5.2, Pharmacokinetic properties).
This product contains lactose.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per dose (maximum daily dose), that is to say essentially ‘sodium-free’.
Concurrent administration with other protein bound drugs may require adjustment in their dosage.
Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see section 4.4, Special warnings and precautions for use). Concurrent administration of mefenamic acid with oral anticoagulant drugs requires careful prothrombin time monitoring.
It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless direct medical supervision.
Lithium: A reduction in renal lithium clearance and an elevation of plasma lithium levels. Patients should be observed carefully for signs of lithium toxicity.
The following interactions have been reported with NSAIDS but have not necessarily been associated with Alfoxan:
Other analgesics: Concomitant use of two or more NSAIDs (including aspirin) should be avoided (see section 4.3, Contraindications).
Antidepressants: Selective serotonin re-uptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4, Special warnings and precautions for use).
Antihypertensives and diuretics: A reduction in antihypertensive and diuretic effect has been observed. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
ACE inhibitors and angiotensin-II receptor antagonists: 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.
Aminoglycosides: Reduction in renal function in susceptible individuals, decreased elimination of aminoglycoside and increased plasma concentrations.
Anti-platelet agents: Increased risk of gastrointestinal bleeding (see section 4.4, Special warnings and precautions for use).
Acetylsalicylic Acid: Experimental data implies that mefenamic acid interferes with the anti-platelet effect of low-dose aspirin when given concomitantly, and thus may interfere with aspirin’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.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure and increases in plasma cardiac glycoside levels may occur when renal function is affected.
Cyclosporin: The risk of nephrotoxicity of cyclosporin may be increased with NSAIDs.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4, Special warnings and precautions for use).
Oral hypoglycaemic agents: Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia.
Mifepristone: NSAIDs should not be taken for 8-12 days after mifepristone administration, NSAIDs can reduce the effects of mifepristone.
Methotrexate: Elimination can be reduced resulting in increased plasma levels.
Probenecid: Reduction in metabolism and elimination of NSAID and metabolites.
Quinolone antibiotics: Animal data indicated that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolone may have an increased risk of developing convulsions.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Safety in pregnancy has not been established and because of the effects of drugs in this class on the foetal cardiovascular system, the use of mefenamic acid in pregnant women is not recommended (see Section 4.3 Contraindications).
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 (see Section 4.3 Contraindications).
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 appears to be the most common side effect and is usually dose-related. It generally subsides on dosage reduction, and rapidly disappears on termination of therapy. Some patients may not be able to continue therapy.
Frequency of reactions: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to ≤1/100); rare (≥1/10,000 to ≤1/1000); very rare (≤1/10,000), not known (cannot be estimated from the available data).
Frequency not known: autoimmune haemolytic anaemia (see section c, Information characterising individual serious and/or frequently occurring adverse reactions), 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.
Rare: agranulocytosis, aplastic anaemia, eosinophilia, neutropenia, pancytopenia.
Frequency not known: anaphylaxis.
Frequency not known: glucose intolerance in diabetic patients, hyponatraemia.
Frequency not known: nervousness.
Frequency not known: aseptic meningitis, blurred vision, convulsions, dizziness, drowsiness, headache and insomnia.
Frequency not known: eye irritation, reversible loss of colour vision.
Frequency not known: ear pain.
Frequency not known: palpitations.
Frequency not known: hypotension.
Frequency not known: asthma, dyspnoea.
Frequency not known: abdominal pain, diarrhoea (see section c, Information characterising individual serious and/or frequency occurring adverse reactions) and nausea with or without vomiting.
Less frequent: anorexia, colitis, constipation, dyspepsia, enterocolitis, flatulence, gastric ulceration with or without haemorrhage, pancreatitis, steatorrhoea.
Frequency not known: borderline elevations of one or more liver function tests, cholestatic jaundice.
Less frequent: mild hepatotoxicity, hepatitis, hepatorenal syndrome.
Frequency not known: angioedema, laryngeal oedema, erythema multiforme, face oedema, Lyell’s syndrome (toxic epidermal necrolysis), perspiration, rash, Stevens-Johnson syndrome, photosensitivity reaction and urticarial.
Frequency not known: allergic glomerulonephritis, acute interstitial nephritis, dysuria, haematuria, nephrotic syndrome, non-oliguric renal failure (particularly in dehydration), proteinuria, renal failure including renal papillary necrosis.
Very rare: multi-organ failure, pyrexia.
Reversible haemolytic anaemia: Reports are associated with ≥12 months of mefenamic acid therapy and the anaemia is reversible with discontinuation of treatment.
Diarrhoea: Although this may occur soon after starting treatment, it may also occur after several months of continuous use. If diarrhoea persists then inflammatory bowel disease should be excluded; if present mefenamic acid must be stopped.
Note: 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 metabolite and not to the presence of bile.
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 © assorted skin disorders including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative or bullous dermatoses, including epidermal necrolysis, toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme and Stevens-Johnson syndrome.
Visual disturbances, optic neuritis, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as Systemic Lupus Erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4, Special warnings and precautions for use), depression, confusion, hallucinations, tinnitus, vertigo, malaise, fatigue and drowsiness.
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) (see section 4.4, Special warnings and precautions for use).
The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4, Special warnings and precautions for use). 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.
Renal toxicity has been seen in patients with pre-renal conditions leading to a reduction in renal blood flow or blood volume. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly.
Reporting suspected adverse reactions after authorization 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 national reporting system.
Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Fax: +357 22608649, Website: www.moh.gov.cy/phs.
Not applicable.
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