SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

POM product Ebufac. P product Migrafen 400

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Ibuprofen BP 400mg

3    PHARMACEUTICAL FORM

Tablet (sugar coated).

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

For the POM product (Ebufac):

a)    The treatment of rheumatoid arthritis (including Still's Disease), osteoarthrosis, ankylosing spondylitis, seronegative (non rheumatoid) arthropathies, bursitis, tenosynovitis, tendonitis and capsulitis (frozen shoulder).

b)    The treatment of soft tissue injuries, particularly strains and low back pain.

c)    The symptomatic relief of migraine, headaches, rheumatic pain, muscular pain, backache, period pain dental pain, neuralgia, colds and flu.

d)    The lowering of body temperature in feverish conditions

For the P product (Migrafen 400):

a)    The symptomatic relief of migraine, headaches, rheumatic pain, muscular pain, backache, period pain dental pain, neuralgia, colds and flu.

b)    The lowering of body temperature in feverish conditions

4.2 Posology and method of administration For the POM product:

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

Adults:    600 mg to 1200 mg daily. Severe conditions up to 1600 mg daily.

Children:    20 mg/kg body weight. In those weighing less than 30 kg total in 24

hours should not exceed 500 mg.

Elderly:    Dosage in the elderly will be as for the adult dose. The elderly are at

increased risk of serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest dose should be used and the patient should be monitored for GI bleeding for 4 weeks following initiation of NSAID.

For the P product:

Adults and children over 12 years: 1 tablet to be taken with water. Subsequently, 1 tablet every four to six hours.

If in adolescents (between 12 and 18 years) this medicinal product is required for more than 3 days, or if symptoms worsen a doctor should be consulted.

Maximum daily dose: three tablets in 24 hours. To be taken preferably after food.

Not to be given to children under 12 years of age.

4.3 Contraindications

Hypersensitivity to any of the constituents. Hypersensitivity to aspirin and other NSAIDs including asthma, rhinitis or urticaria. Current or previous peptic ulceration or severe heart failure.

Not for use by children under the age of 12 without medical advice if sold as a P product.

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).

Cardiovascular and cerebrovascular effects

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 increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. < 1200mg daily) is associated with an increased risk of myocardial infarction.

[Ebufac] 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.

[Ebufac] 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, smoking).

In patients with a history of cardiac de-compensation of hypertension, ‘Migrafen 400 /Ebufac’ should be used with caution because fluid retention and oedema have been reported in association with Ibuprofen.

Acute interstitial nephritis with haematuria, proteinuria and, occasionally, nephrotic syndrome has been reported.

In some patients, particularly those with pre-renal conditions leading to a reduction in renal blood flow or volume, and where the renal prostaglandins play a part in the maintenance of renal perfusion, the administration of an NSAID may cause a dose-dependant reduction in prostaglandin formation and this may precipitate a renal decompensation. At greatest risk of this reaction are patients with impaired renal function, heart failure, liver dysfunction, the elderly and patients taking diuretics. Discontinuation of NSAIDs is associated with recovery to the pre-treatment state.

Patients with impaired renal function should be closely monitored and a reduction in dosage should be used in order to avoid drug accumulation because Ibuprofen is eliminated mainly by the kidneys.

All patients who are at risk of developing renal dysfunction during long-term treatment should be monitored for renal function periodically.

There is a risk of renal impairment in dehydrated children and adolescents.

It is advisable that patients receiving ‘Migrafen 400 /Ebufac’ should report to their physician at signs or symptoms of gastro-intestinal ulceration or bleeding, or any eye symptoms such as blurred vision, oedema, weight gain or skin rash.

All patients with a history of upper gastro-intestinal tract disease should be kept under close supervision when receiving ‘Migrafen 400 / Ebufac’.

In patients suffering from, or with a history of, bronchial asthma, ‘Migrafen 400 / Ebufac’ should be used with extreme caution since ibuprofen has been reported to cause bronchospasm in such patients.

Treatment should be discontinued in patients reporting ocular defects such as diminished vision, blurred vision, changes in colour vision or scotomata.

Gastro-intestinal bleeding and peptic ulceration have been reported in those patients receiving Ibuprofen.

In patients with renal, cardiac or hepatic impairment caution is required since the use of NSAIDs may result in deterioration of renal function. The dose should be kept as low as possible and renal function should be monitored.

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

NSAIDs have been reported to cause nephrotoxicity in various forms and their use can lead to interstitial nephritis, nephrotic syndrome and renal failure.

Undesirable effects can be minimised by using the lowest effective dose for the minimum time required.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent aspirin or other NSAIDs may result in an increased incidence of adverse reactions.

Anti-coagulants: May enhance the effects of anti-coagulants.

Anti-hypertensives :NSAIDs may diminish the effect of anti-hypertensives.

Diuretics: Reduced diuretic effect.

Diuretics can increase the risk of nephrotoxicity of NSAIDs. Cardiac glycosides: NSAIDs may exacerbate renal failure, reduce GFR and increase plasma glycoside levels.

Cyclosporin: Increased risk of nephrotoxicity.

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

Corticosteroids: Increased risk of GI bleeding.

Quinolone antibiotics: Animal data indicate that NSAIDS can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDS and quinolones may have increased risk of developing convulsions.

Frusemide: Ibuprofen reduces the natriuretic effect of frusemide and thiazide diuretics. This is thought to be due to the inhibition of renal prostaglandin synthesis. Patients being treated concomitantly with Ibuprofen and thiazides or frusemide.

Should be closely monitored.

Lithium: Patients receiving ibuprofen and lithium should be closely observed for signs of lithium toxicity because Ibuprofen has been shown to produce an elevation of plasma lithium levels and a reduction in renal lithium clearance.

Methotrexate: When methotrexate is used concomitantly with ibuprofen, enhanced toxicity of methotrexate may ensue due to a reduction of renal tubular secretion of methotrexate. Exercise caution in these circumstances.

4.6 Pregnancy and lactation

Whilst no teratogenic effects have been demonstrated in animal studies, ibuprofen should be avoided during pregnancy. Congenital abnormalities have been reported in association with ibuprofen administration in man associated; 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, closure of ductus arteriosus, use in late pregnancy should be avoided. The onset of labour may be delayed and the duration of labour increased. Ibuprofen appears in breast milk at very low concentrations and is unlikely to affect the breast fed infant adversely.

4.7 Effects on ability to drive and use machines

Migrafen 400/Ebufac' does not affect the ability to drive or use machines.

4.8 Undesirable effects

Gastro-intestinal: the most commonly-observed adverse events are gastrointestinal in nature. Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis and gastrointestinal haemorrhage have been reported following administration. Less frequently, gastritis, duodenal ulcer, gastric ulcer and gastritis, duodenal ulcer, gastric ulcer and gastrointestinal perforation have been observed.

Skin: Rashes, pruritis, urticaria. Rarely exfoliative dermatitis and epidermal necrolysis have been reported with ibuprofen.

Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reaction and anaphylaxis, (b) respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular: Clinical trial and 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 (for example myocardial infarction or stroke) (see section 4.4). Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Other adverse events reported less commonly include:

Dermatological: Photosensitivity may occur

Haematological: Thrombocytopenia.

Renal: Papillary necrosis which can lead to renal failure.

Hepatic: Abnormal liver function, hepatitis and jaundice

Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

4.9 Overdose

Symptoms include headache, vomiting, drowsiness and hypotension. Gastric lavage and correction of electrolytic abnormalities should be considered.

Nausea, epigastric spin, non-specific rash, dizziness, elevated serum creatinine levels, anaemia

In some 20% of patients there is a decrease in haemoglobin concentration content.

Rarely occurring adverse reactions are renal failure, lupus erythematosus syndrome with aseptic meningitis, abnormal liver function tests, jaundice, blood dyscrasias including thrombocytopenia. Meningitis is more common in patients with systemic lupus erythematosus and related connective tissue disease.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Ibuprofen is a phenylpropionic acid derivative with analgesic, anti-inflammatory and antipyretic actions. Ibuprofen inhibits prostaglandin synthesis.

It is a white powder with characteristic odour and a melting point 75°-77.5°C. Ibuprofen is practically insoluble in water but soluble in 1.5 of alcohol and 1 of chloroform, 1 in 2 of ether and 1 in 1.5 of acetone. Soluble in aqueous solutions of alkali hydroxides and carbonates.

5.2 Pharmacokinetic properties

Ibuprofen is absorbed from the gastro-intestinal tract. Peak plasma concentrations occur about one to two hours after ingestion. The drug is extensively bound to plasma proteins and has a half life of about 2 hours. It is rapidly excreted in the urine, mainly in the form of metabolites and their conjugates. About 1% is excreted in urine as unchanged Ibuprofen and about 14% as conjugated Ibuprofen.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

In the core:

Pregelatinised maize starch

Crospovidone

Talc

Colloidal anhydrous silica Stearic acid Magnesium stearate Purified water

In the coating :

Shellac Talc Povidone 25 Opalux AS-1320 Titanium dioxide Sucrose Beeswax Carnauba wax

6.2 Incompatibilities

No known incompatibilities other than those stated in 4.4 and 4.5 above.

6.3 Shelf life

The shelf-life of Ibuprofen tablets 400mg as packaged for sale is: 36 months in plastic containers 24 months in blister-packs

6.4 Special precautions for storage

Store below 25°C in a dry place in well closed containers.

Nature and contents of container

1.    High density polystyrene with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane or polythene inserts. Packs of 3, 6, 12, 24, 28, 30, 50, 56,100, 500, 1000 tablets.

2.    PVC aluminium foil blister packs, composed of 25 micron PVC glass clear/bluish rigid PVC (pharmaceutical grade) and 20 micron hard-tempered aluminium foil coated on the pull side with 6.7gsm heat-seal lacquer and printed on the bright side. The blister strips are enclosed in outer cardboard cartons. Blister-packs are of 3, 6, 12, 24, 28, 48, 84, 96, 100, 500, 1000 tablets.

The label for the P product will state: “Do not use if you have ever had a stomach ulcer or are allergic to ibuprofen or aspirin. If you are allergic to, or are taking any other pain killer, are pregnant or suffer from asthma, speak to your doctor before taking ‘Migrafen 400’”.

The leaflet for the P Product will state: “If your symptoms persist, consult your doctor of pharmacist.”

6.6 Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited 11 Boumpoulinas Street,

3^rd floor, 1060 Nicosia Cyprus

8    MARKETING AUTHORISATION NUMBER(S)

PL 33414/0050

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 04 December 1979

10 DATE OF REVISION OF THE TEXT

29/01/2016