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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Ibular Tablets 400mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 400mg of Ibuprofen

3    PHARMACEUTICAL FORM

Coated Tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ibular is indicated for its anti-inflammatory and analgesic effect in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or still's disease), ankylosing spondylitis, osteoarthrosis and other nonrheumatoid (sero-negative) arthropathies. In treatment of non-articular rheumatic conditions Ibular is indicated in periarticular conditions such as capsulitis, bursitis tendinitis, tenosynovitis and low back pain: it can also be used in soft tissue injuries such as sprains and strains. Ibular may be taken on an empty stomach without gastric discomfort - a valuable aid to relieving early morning stiffness.

4.2    Posology and method of administration

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

Adults: Recommended initial dosage of Ibular is 1,200mg daily in divided doses. Some patients can be maintained on 600 - 1200mg daily. In severe conditions dosage can be increased to 1600mg daily in divided doses until the acute phase is brought under control.

Children: 20mg ibuprofen per kg of body weight daily. Children weighing less than 30kg - total dose of Ibular in 24 hours should not exceed 500mg.

4.3    Contraindications

Patients who have previously shown hypersensitivity reactions (e.g. asthma, urticaria, angioedema or rhinitis) after taking ibuprofen, aspirin or other NSAIDs.

Patients with a hypersensitivity to the active substance or to any of the excipients.

Severe heart failure, hepatic failure and renal failure (see section 4.4).

Patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy. Ibular should not be used in patients with active, or history of, recurrent peptic ulcer or gastrointestinal haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

During the last trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

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

As with other NSAIDs, ibuprofen may mask the signs of infection.

The use of Ibular with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided due to the potential for additive effects (see section 4.5).

The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal (see section 4.2).

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.

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), 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 section 4.5).

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

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-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving Ibular, the treatment should be withdrawn.

NSAIDs should be given with care to patients with a history of ulcerative colitis or Crohn's disease as these conditions may be exacerbated (see section 4.8).

Respiratory disorders

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

Cardiovascular, renal and hepatic impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of 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).

Ibular should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with ibuprofen administration.

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 data suggest that use of ibuprofen, particularly at a high dose (2400mg daily) and in long term treatment may be associated with a small increase risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that a low dose ibuprofen (e.g. <1200mg daily) is associated with an increased risk of arterial thrombotic events, particularly myocardial infarction.

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

Renal effects

Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration.

As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependant reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.

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 below and section 4.8).

Dermatological effects

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 the 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 within the first month of treatment in the majority of cases. Ibular should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Haematological effects

Ibuprofen, like other NSAIDs, can interfere with platelet aggregation and has been shown to prolong bleeding time in normal subjects.

Aseptic meningitis

Aseptic meningitis has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systematic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease.

Impaired female fertility

The use of Ibular 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 Ibular should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effects is considered to be likely for occasional ibuprofen use (see section 5.1).

As with other NSAIDs, caution should be exercised in patients who are receiving any of the following drugs:

Anti-hypertensives (e.g. ACE inhibitors, Beta Blockers): risk of antagonism or anti-hypertensive effect.

Antibacterials: Quinolone antibiotics: Animal data indicate 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.

Anticoagulants: Increased risk of haemorrhage, prothrombin time should be monitored daily for the first few days of combined treatment.

Aspirin: As with other products containing NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential of increased adverse effects.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding with NSAIDs (see section 4.4).

Aminoglycosides: NSAIDs may decrease the excretion of aminoglycosides.

Herbal extracts: Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.

Corticosteroids: Increased risk of gastro-intestinal bleeding and ulceration with NSAIDs (see section 4.4).

Diuretics: Risk of nephrotoxicity increased and may antagonise the diuretic effect.

Lithium: Reduced excretion of lithium.

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

Ciclosporin: Increased risk of nephrotoxicity.

Methotrexate (cytotoxics): Excretion of methotrexate reduced.

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

Other analgesics and cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs, including Cox-2 inhibitors, as this may increase the risk of adverse effects (see section 4.4).

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.

4.6 Fertility, pregnancy and lactation

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). 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.

Lactation

In the limited studies so far available, NSAIDs can appear in the breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and GI and cardiovascular risks below).

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 (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following ibuprofen administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reaction 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 and bullous dermatoses (including Stevens- Johnson syndrome, toxic epidermal necrolysis and erythema multiforme).

Cardiac disorders and vascular disorders: 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 NS AID therapy. Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Epidemiological data suggest that use of ibuprofen, particularly at high dose (2400 mg/ daily), and in long term treatment, may be associated with a small increased risk of arterial thrombotic events such as myocardial infarction or stroke (see section 4.4).

Other adverse events reported less commonly and for which causality has not necessarily been established include:

Blood and lymphatic system disorders: Thrombocytopenia, neutropenia, eosinophilia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Psychiatric disorders: Depression, confusional state, hallucination.

Nervous system disorders: Optic neuritis, headache, paraesthesia, dizziness, somnolence, insomnia, nervousness, drowsiness.

Aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue disease) with symptoms of stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4).

Eye disorders: Visual disturbance including blurred vision, changes in visual colour perception, toxic amblyopia.

Ear and labyrinth disorders: Tinnitus, vertigo.

Hepatobiliary disorders: Abnormal liver function, hepatic failure, hepatitis and jaundice.

Skin and subcutaneous tissue disorders: Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), and photosensitivity reaction.

Renal and urinary disorders: Impaired renal function and toxic nephropathy in various forms, including interstitial nephritis, nephrotic syndrome, renal failure, cystitis and haematuria.

General disorders and administration site conditions: Malaise, fatigue. 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.

4.9 Overdose

In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5.1    Pharmacodynamic properties

Ibuprofen has analgesic, anti-inflammatory and anti-pyretic properties; it is an inhibitor of prostaglandin synthetase.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 hours before or within 30 minutes after immediate release aspirin dosing (81mg), a decreased effect of aspirin on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be like for occasional ibuprofen use.

5.2    Pharmacokinetic properties

A bioavailability study carried out with eight healthy subjects administered 400mg Ibular, gave the following:

t/ (hours): 1.878 ± 0.232

time to peak (hours): 1.947 ± 0.124

peak concentration (pg/ml): 22.477 ± 0.964

AUC12 (pg/ml/hours): 122.267 ± 7.921*

AUC (pg/ml/hours): 127.07 ± 9.187 * = p<0.05

5.3    Preclinical safety data

Not applicable

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose Povidone Maize starch Purified talc Magnesium stearate Colloidal Hydrated Silica Carmellose sodium

Coat:

Povidone

Gelatin

Macrogol 1540 Calcium carbonate Purified talc

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