SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Flurbiprofen 100 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100mg Flurbiprofen

Excipients with known effect: Also contains sucrose 164.80mg, Glucose 3mg, Lactose anhydrous 75mg and sunset yellow (E110).

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Coated Tablets

The tablets are sugar coated and yellow in colour.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of rheumatoid disease, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and trauma such as periarthritis, frozen shoulder, bursitis, tendinitis, tenosynovitis, low back pain, sprains and strains.

Flurbiprofen is also indicated for its analgesic effect in the relief of mild to moderate pain in conditions such as dental pain, post-operative pain, dysmenorrhoea and migraine.

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:

150 to 200 mg daily in two, three or four divided doses. In patients with severe symptoms of disease of recent origin, or during acute exacerbations, the total daily dosage may be increased to 300mg in divided doses.

For dysmenorrhoea, a dosage of 100mg may be administered at the start of symptoms, followed by 50 or 100 mg given at four - to six - hourly intervals.

The maximum total daily dosage should not exceed 300mg.

Children:

Flurbiprofen is not recommended for use in children under 12 years.

Elderly:

The elderly are at risk of the serious consequences of adverse reactions. Although flurbiprofen is generally well tolerated in the elderly, some patients, especially those with impaired renal function, may eliminate NSAIDs more slowly than normal. In these cases, flurbiprofen should be used with caution and dosage should be assessed individually.

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.

Method of administration For oral use.

To be taken preferably with or after food.

4.3 Contraindications

Flurbiprofen is contraindicated in patients with hypersensitivity (asthma, urticaria or allergic type) to flurbiprofen or to any of the inactive ingredients.

Flurbiprofen is also contra-indicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to flurbiprofen, aspirin or other NSAIDs.

Flurbiprofen is also contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy.

Flurbiprofen should not be used in patients with active, or history of ulcerative colitis, Crohn’s disease, recurrent peptic ulcer or gastro-intestinal haemorrhage (defined as two or more distinct episodes of proven ulceration or bleeding).

Flurbiprofen is contraindicated in patients with severe heart failure, hepatic failure and renal failure (see section 4.4).

4.4 Special warnings and precautions for use

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

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

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)

Gastrointestinal bleeding, ulceration and perforation:

GI bleeding, ulceration or perforation, 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 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 ).

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

Flurbiprofen should only 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).

Respiratory Disorders:

Caution is required if flurbiprofen is administered to patients suffering from, with a previous history of, bronchial asthma since NASIDs have been reported to cause 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 section 4.3).

Flurbiprofen should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with flurbiprofen 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 flurbiprofen administration and NSAID therapy.

Clinical trial 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 such as myocardial infarction or stroke. There are insufficient data to exclude such a risk for flurbiprofen.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with flurbiprofen 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).

Renal effects

Caution should be used when initiating treatment with NSAIDs such as flurbiprofen in patients with considerable dehydration.

Other effects:

Caution is required in patients with renal, hepatic or cardiac impairment 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 in these patients.

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).

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

Haematological effects:

Flurbiprofen, like other NSAIDs, may inhibit platelet aggregation and prolong bleeding time. Froben should be used with caution in patients with a potential for abnormal bleeding.

Impaired Female fertility:

The use of flurbiprofen 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 flurbiprofen should be considered.

Flurbiprofen tablets contain sunset yellow which can cause allergic -type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

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

4.5 Interactions with other medicinal products and other forms of interaction

Care should be taken in patients treated with any of the following drugs as interactions have been reported in some patients.

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

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking flurbiprofen concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium salts: Decreased elimination of lithium.

Methotrexate: Caution is advised in the concomitant administration of flurbiprofen and methotrexate since NSAIDs may increase methotrexate levels.

Ciclosporin: Increased risk of nephrotoxicity with NSAIDs.

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

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding with NSAIDs (see section 4.4).

Anti-coagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin (see section 4.4).

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

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.

Selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding with NSAIDs (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 other NSAIDs.

Studies have failed to show any interaction between flurbiprofen and tolbutamide or antacids. There is no evidence so far that flurbiprofen interferes with standard laboratory tests.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, flurbiprofen should not be given unless clearly necessary. If flurbiprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

•    cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

•    renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

•    possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

•    inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, flurbiprofen is contraindicated during the third trimester of pregnancy.

Lactation:

In the limited studies so far available, NSAIDs can appear in the breast milk in very low concentrations. Flurbiprofen is not recommended for use in nursing mothers.

See section 4.4 - Special Warnings and Precautions for Use, regarding female fertility.

4.7    Effects on ability to drive and use machines

Flurbiprofen may cause confusional states, fatigue, hallucinations, dizziness, somnolence and visual disturbances. The patient should be warned that if affected they should not drive, operate machinery or take part in activities where these may put themselves or others at risk.

4.8    Undesirable effects

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, gastrointestinal haemorrhage, exacerbation of colitis and Crohn’s disease (see section 4.3 & 4.4) have been reported following flurbiprofen administration. Less frequently, gastritis, = and ulcer haemorrhage have 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 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, angioedema and, more rarely, exfoliative and bullous dermatoses (including toxic epidermal necrolysis and erythema multiforme ).

Cardiac disorders and vascular disorders :

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).

Respiratory, thoracic and mediastinal disorders:

Respiratory tract reactivity (asthma, bronchospasm, dyspnoea).

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

Blood and lymphatic system disorders:

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

Psychiatric disorders:

Depression, confusional state, hallucination.

Nervous system disorders:

Cerebrovascular accident, optic neuritis, headache, paraesthesia, dizziness, and somnolence.

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

Ear and labyrinth disorders:

Tinnitus, vertigo

Renal and urinary disorders:

Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.

Hepatiobiliary disorders:

Abnormal liver function, hepatitis and jaundice.

Skin and subcutaneous tissue disorders:

Skin disorders including rash, pruritis, urticaria, purpura and very rarely, bullous dermatoses (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme) and photosensitivity reaction.

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

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions and rarely, loss of consciousness. In cases of significant poisoning acidosis, acute renal failure and liver damage are possible. An increase in INR may also occur. Exacerbation of asthma is possible.

Management

•    Ingestion of small amounts should not require treatment

•    There is no specific antidote to Flurbiprofen

•    The benefit of gastic decontamination is uncertain. Consider activated charcoal (50g adults: 1g/kg for children) if the patient presents within one 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.

•    Observe patients for at least 4 hours after ingestion of a potentially toxic amounts

•    Measure FBC, U+Es and creatinine. Monitor kidney and liver function and treat failure conventionally. Good urine output should be ensured.

•    Convulsions

•    Give oxygen, check blood glucose, U+Es and AGB

•    A single brief convulsion does not require treatment

•    If frequent or prolonged control with IV diazepam or larazepam

•    If unresponsive discuss with local poisons information service (UK NPIS: Ireland NPIC)

•    Give bronchodilators for asthma

•    Other measures as indicated by the patient’s condition

•    On discharge, patients should be advised to seek medical attention if symptoms develop

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and anti-rheumatic products, propionic acid derivatives, ATC Code MO1A E09.

Flurbiprofen has analgesic, anti-inflammatory and antipyretic properties. These are thought to result from the drugs ability to inhibit prostaglandin synthesis.

5.2 Pharmacokinetic properties

Flurbiprofen is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 90 minutes after ingestion. It is about 99% protein-bound and has an elimination half-life of about 3-4 hours.

The rate of urinary excretion of flurbiprofen and its two major metabolites ([2-(2-fluoro-4’-hydroxy-4-biphenyl) propionic acid and ([2-(2-fluoro-3'-hydroxy-4'-methoxy-4-biphenyl) propionic acid]) in both the free and conjugated states is similar for both the oral and the rectal routes of administration. Metabolic patterns are also quantitatively similar for both routes of administration.

5.3 Preclinical safety data

Not applicable.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose,

Lactose,

Maize starch,

Titanium dioxide,

Povidone,

Liquid glucose,

Magnesium stearate,

Stearic acid,

Colloidal anhydrous silica,

French chalk for tablets,

Quinoline yellow,

Ssandarac tablet varnish,

Carnauba wax,

Sunset yellow,

Sodium benzoate.

Incompatibilities

Not applicable

6.3 Shelf life

Blister pack: 36 months

6.4 Special precautions for storage

Blister pack: Store in the original package.

6.5 Nature and contents of container

A PVC/aluminium blister pack containing 10 tablets per strip. Pack sizes: 10, 30, 100 and 500 tablets.

6.6 Special precautions for disposal

No special requirement

7 MARKETING AUTHORISATION HOLDER

Bristol Laboratories Limited Unit 3 Canalside Northbridge road Berkhamsted HP4 1EG UK

MARKETING AUTHORISATION NUMBER(S)

PL 17907/0325

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 25/03/2009

10 DATE OF REVISION OF THE TEXT

Date of variation approval