Chemidex Pharma Ltd

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.

Section 2 Added: For a full list of excipients, see section 6.1

Section 4.2 The following changed Children It is recommended that children under 12 years of age should be given Mefenamic Acid Suspension (50mg/5ml).

Section 4.3 Bronchospasm added as a hypersensitivity reaction 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, angiooedema angioedema or urticaria) to these medicines. Added: Treatment of pain after coronary artery bypass graft (CABG) surgery. Deleted: Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (See section 4.5 Interactions). Deleted Intestinal ulceration or inflammation

Section 4.4 Added: 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 stop therapy immediately (see section 4.8) And added: As NSAIDs can interfere with platelet function, they should be used in caution in patients with intracranial haemorrhage and bleeding diasthesis. And added risk factors for GI bleeding thus: Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Smoking and alcohol use are added risk factors. And deleted: NSAIDs should be given with care to patients with a history of gastrointestinal disease (e.g ulcerative colitis, Crohn’s Disease) as these conditions may be exacerbated. (see section 4.8 – Undesirable effects) Added section on skin reactions 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 (see section 4.8). 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. Added excipient warning (Capsules only) Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Section 4.5 Amended text for anticoagulants Added interactions for : Antidepressants - Selective serotonin reuptake inhibitors (SSRIs) ACE inhibitors and angiotensin-II-receptor antagonists: Aminoglycosides Anti-platelet agents: Oral hypoglycaemic agents Probenecid:

Section 4.8 Section reorganised into body systems Added terms: toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, renal failure, bone marrow hypoplasia, anaemia and decreased haematocrit, leukopenia with a risk of infection, sepsis, and disseminated intravascular coagulation, blurred vision, eye irritation, reversible loss of colour vision, ear pain, convulsions, insomnia, anorexia, mild hepatic toxicity, hepatitis, hepatorenal syndrome, colitis, enterocolitis, steatorrhoea, facial oedema, laryngeal oedema, hyponatraemia, nervousness, perspiration, pyrexia, multi-organ failure

Section 4.9 Added: It is important that the recommended dose is not exceeded and the regime adhered to since some reports have involved daily dosages under 3g. Added: Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins

Section 6.1 Amended spelling of sodium lauryl sulphate to sodium laurilsulfate.

In 4.2 Posology and method of administration

Addition of: Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4)

In 4.4. Special warnings and precautions for use

SECTION 4.2 (Posology and method of administration)

Addition of the following text:

For oral administration

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.

Ponstan Forte tablets should be taken preferably with or after food.

SECTION 4.3 (Contraindications)

Deletion of crossed-through text. Addition of bold underlined text.

Patients hypersensitive to mefenamic acid or any of the other ingredients.

 Mefenamic acid is contra-indicated in inflammatory bowel disease and in patients suffering from active or previous peptic and/or intestinal ulceration or history of upper gastrointestinal bleeding or perforation related to previous NSAIDs therapy. and in patients with renal or hepatic impairment.

Severe hepatic, renal and cardiac failure (See section 4.4 –Special warnings and precautions for use).

Because the potential exists for cross-sensitivity to aspirin, ibuprofen, or other non-steroidal anti-inflammatory drugs, mefenamic acid should not be given to patients who have previously shown hypersensitivity reaction (e.g asthma, rhinitis angiooedema or urticaria) to these medicines in whom these drugs induce symptoms of bronchopsasm, allergic rhinitis, or urticaria.

During the last trimester of pregnancy (See section 4.6 – Pregnancy and lactation)

Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (See section 4.5 Interactions).

SECTION 4.4 (Special warnings and precautions for use)

Deletion of crossed-through text. Addition of bold underlined text.

In all patients: Undesirable effects may be minimised by using the minimum effective dose for the shortest possible duration

Precaution should be taken in patients suffering from dehydration and renal disease, particularly the elderly.

Elderly: 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 administration)

Respiratory disorders: 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

Cardiovascular, Renal and hepatic impairment:  The administration of an NSAID may cause a dose dependant reduction in prostaglandin formation and precipitate renal failure.  Patients at greatest riskof this reaction are those with impaired renal function,cardiac impairment, liver dysfunction, those taking diuretics and the elderly  Renal function should be monitored in these patients (see also section 4.3 – Contraindications).

Caution in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Gastrointestinal bleeding, ulceration and perforation: GI belleding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

 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, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5 Interactions)

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

NSAIDs should be given with care to patients with a history of gastrointestinal disease (e.g ulcerative colitis, Crohn’s Disease) as these conditions may be exacerbated. (see section 4.8 – Undesirable effects)

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 (See section 4.8 – Undesirable effects).

Female fertitity: The use of mefenamic acid may impair femaole fertility and is not recommended in women attempting to conceive.  In women who have difficulties conceiving or who are undergoing investigation of infertitilty, withdrawal of mefenmaic 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.

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

SECTION 4.5 (Interaction with other medicaments and other forms of interaction)

Deletion of crossed-through text. Addition of bold underlined text.

Change from cyclosporin to INN ciclosporin

Concurrent therapy with other plasma protein binding drugs may necessitate a modification in dosage.  In the case of anticoagulants the dose of the anticoagulant may need to be reduced.  Concurrent administration of mefenamic acid with oral anticoagulant drugs requires careful prothrombin time monitoring.

The following interactions have been reported with NSAIDS but have not necessarily been associated with Ponstan Tablets:

Other analgesics: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (See section 4.3 – Contraindications)

Antihypertensives and diuretics: a reduction in antihypertensive and diuretic effect has been observed. Diuretics can increase the nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increases in plasma cardiac glycoside levels may occur when renal function is affected.

Lithium and methotrexate: Elimination of these drugs can be reduced.

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

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

Corticosteroids: Concomitant use may increase the risk of gastrointestinal bleeding. (see section 4.4 – Special warnings and precautions for use)

Quinolone antibiotics: 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.

Other analgesics: Concomitant use of two or more NSAIDs should be avoided.

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

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SECTION 4.6 (Pregnancy and lactation)

Deletion of crossed-through text. Addition of bold underlined text.

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.

Pregnancy:  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 (See section 4.3 Contraindications).  NSAIDs should not be used during the first two trimesters of pregnancy or labour unlessthe potential benefit to the patient outweighs the potential risk to the foetus.

Lactation: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 4.4 Special warnings and precautions for use regarding female fertility.

SECTION 4.7 (Effects on ability to drive and use machines)

Deletion of crossed-through text. Addition of bold underlined text.

Drowsiness and dizziness have rarely been reported.

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

SECTION 4.8 (Undesirable effects)

Deletion of crossed-through text. Addition of bold underlined text.

Gasrointestinal: The most commonly-observed adverse events are gastro-intestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). 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. 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.

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

Skin rashes have been observed following the administration of mefenamic acid and the occurrence of a rash is a definite indication to withdraw medication.  There have been rare reports of Steven-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis) and erythema multiforme.

Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time with or without warning symptoms, in patients treated chronically with NSAID therapy.  GI bleeding has been associated with a previous history of peptic ulcer, smoking and alcohol use.

Hypersensitivity: 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, angiodema, and more rarely exfoliative or bullous dermatoses (including epidermal necrolysis and erythema multiforme)  

Cardiovascular: Oedema has been reported in association with NSAID treatment.

Other less common adverse events

As with other prostaglandin inhibitors allergic glomerulonephritis has occurred occasionally.  There have also been reports of acute interstitial nephritis with haematuria and proteinuria and occasionally nephrotic syndrome.  Non-oliguric renal failure has been reported on a few occasions in elderly patients with dehydration usually from diarrhoea.  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.  The drug should not be administered to patients with significantly impaired renal function.  It has been suggested that the recovery is more rapid and complete than with other forms of analgesic induced renal impairment, with discontinuation of NSAID therapy being typically followed by recovery to the pre-treatment state.

Thrombocytopenic purpura has been reported with mefenamic acid.  In some cases reversible haemolytic anaemia has occurred.  Temporary lowering of the white blood cell count which may have been due to mefenamic acid has been reported.  Rarely eosinophilia, agranulocytosis, neutropenia, pancytopenia and aplastic anaemia have been reported.  Blood studies should therefore be carried out during long term administration and the appearance of any dyscrasia is an indication to discontinue therapy.

Bronchospasm and/or urticaria may be precipitated in patients suffering from, or with a previous history of, bronchial asthma or allergic disease.

Borderline elevations of one or more liver function tests may occur in some patients receiving mefenamic acid therapy.  A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should have their therapy discontinued.  Patients on prolonged therapy should be kept under surveillance with particular attention to liver dysfunction.  Pancreatitis and cholestatic jaundice have also been reported.

Neurological and special senses: visual disturbances, optic neuritis, headaches, paraesthesia, 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 (see section 4.4), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Other adverse reactions: Nausea, vomiting, abdominal pain, headache, facial oedema, laryngeal oedema and anaphylaxis.  Drowsiness, dizziness, abnormal vision, ,  Photosensitivity reactions, palpitations, Glucose intolerance in diabetic patients and hypotension have rarely been reported.

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 metabolites and not to the presence of bile.

SECTION 4.9 (Overdose)           

Gastric lavage in the conscious patient and intensive supportive therapy where necessary.  Vital functions should be monitored and supported.  Activated charcoal has been shown to be a powerful adsorbent for mefenamic acid and its metabolites.  Studies in experimental animals and human volunteers have shown that a 5 to 1 ratio of charcoal to mefenamic acid results in considerable suppression of absorption of the drug.  Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.  Overdose has led to fatalities.

Mefenamic acid has a tendency to induce tonic-clonic (grand mal) convulsions in overdose.  Acute renal failure and coma have been reported with mefenamic acid overdose.  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 patients clinical condition.

SECTION 9 (Date of First Authorisation/Renewal of Authorisation) and SECTION 10 (Date of Revision of the Text)

 Changed to 10/10/2005