SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fenbid Biphasic 400 mg capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 400 mg of Ibuprofen Ph. Eur.

3 PHARMACEUTICAL FORM

Oral capsules with immediate and sustained release components.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Fenbid is indicated for its analgesic and anti-inflammatory effects in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still’s disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies.

It may also be used in non-articular rheumatic conditions and soft tissue injuries, including low back pain, capsulitis of the shoulder, bursitis, tendinitis, tenosynovitis, dysmenorrhoea, dental and postoperative pain, sprains and strains.

4.2 Posology and method of administration

For oral administration.

To be taken preferably with or after food.

The capsules should be swallowed whole with a liberal quantity of water.

Adults: 1 capsule twice daily. The dose may be increased to two capsules twice daily if necessary. The first should be taken in the morning and the second 8-12 hours later. The capsules should be taken with or after food.

Fenbid is not recommended for children under 12 years of age.

Patients should be instructed not to chew or suck the capsules as this destroys the sustained release properties. Providing this is ensured, the contents of a capsule may be sprinkled onto a spoonful of soft food, yoghurt, or similar substance, for patients who experience difficulty in swallowing the capsule.

Elderly Patients: It would appear that advanced age has minimal influence on the pharmacokinetics of ibuprofen. However the following should be considered:

Ibuprofen has been reported to be associated with cognitive dysfunction in the elderly.

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.

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

4.3 Contraindications

•    Hypersensitivity to Ibuprofen or to any of the excipients listed in section 6.1.

•    NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

•    Severe heart failure (NYHA Class IV^ hepatic-failure and renal failure. (See section 4.4).

•    During the last trimester of pregnancy (See section 4.6)

•    Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

•    History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4. Special warnings and precautions for use

The use of Fenbid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5)

If given to patients receiving anticoagulant therapy, prothrombin time should be monitored at least for the first few days of combined treatment.

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).

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 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 - Contraindications).

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 studies suggest that use of ibuprofen, particularly at a high dose (2400mg/day ) 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 arterial thrombotic events..

Patients with uncontrolled hypertension, congestive heart failure(NYHA II-III),, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided..

Careful consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required..

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAID 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 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 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 Interactions).

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

NSAIDs should be given with care to patients with a history of gastrointestinal disease (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).

Dermatological

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 for 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 Fenbid should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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

Impaired Female fertility:

The use of Ibuprofen 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 or Ibuprofen should be considered.

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)

4.5. Interaction with other medicinal products and other forms of interaction

Fenbid Biphasic Capsules should be avoided in combination with:

Acetylsalicylic acid

Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other analgesics including cyclooxygenase—2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (See section 4.4).

Anti-hypertensives: Reduced anti-hypertensive effect.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

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

Lithium: Decreased elimination of lithium.

Methotrexate: Decreased elimination of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should nt be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteriods: Increased risk of gastrointestinal bleeding (See section 4.4 -Special warnings and precautions for use).

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4 - Special warnings and precautions for use).

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.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) : Increased risk of gastrointestinal bleeding (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 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 Contraindications). 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 limited studies so far available, NSAIDs can appear in 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

Gastrointestinal: 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 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

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, pruritis, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:

Clinical studies suggest that use of ibuprofen, particularly at high dose (2400 mg/day )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 reactions reported less commonly include:

Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic Syndrome and renal failure.

Hepatic: Abnormal liver function, hepatitis and jaundice.

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

Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.

Reporting of suspected adverse reactions

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 Yellow Card Scheme website:www.mhra.gov.uk.uk/yellowcard.

4.9 Overdose

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

a) Symptoms

Symptoms include 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, dizziness, 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.

b) Therapeutic measures

Patients should be treated symptomatically as required.

Management should be supportive and include the maintainance 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. 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.. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

Other measures may be indicated by the patient’s clinical condition.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Ibuprofen is a recognised non-steroidal anti-inflammatory agent with marked analgesic and antipyretic properties.

Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400 mg were taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81 mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding extrapolation of these data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

5.2 Pharmacokinetic properties

The product is a combined immediate release and sustained release formulation of ibuprofen designed to ensure plasma levels in the therapeutic range for approximately 12 hours.

Preclinical safety data

No further information.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sugar spheres USP

(containing maize starch and sucrose)

Povidone BP

Sodium starch glycollate BP

6.2 Incompatibilities

None Known.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store at room temperature below 25°C, protected from light and moisture.

6.5 Nature and contents of container

PVC (200-250pm)/PVDC (40gms) blisters and aluminium foil (20 pm).