Flurbiprofen 100 mg Tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Flurbiprofen 100 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg Flurbiprofen

Excipients with known effect: Also contains sucrose 82.40 mg , glucose 1.3 mg, lactose 37.50 mg 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.

4.2 Posology and method of administration

Posology:

Undesirable effects may be minimised by using the lowest effective dose should be used for the shortest duration necessary to relieve 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.

Paediatric population:

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

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Flurbiprofen is 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 ulceration 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).

Flurbiprofen is contraindicated 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 minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

On prolonged use of any painkiller, headache may occur that must not be treated with increased doses of the medicinal product. Through concomitant consumption of alcohol, active substance-related undesirable effects, particularly those that concern the gastrointestinal tract or the central nervous system, may be increased on use of NSAIDs.

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:

Flurbiprofen should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.

GI bleeding, ulceration or perforation, has been reported with all NSAIDs at any time during treatment. These adverse events can be fatal and may occur 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 flurbiprofen 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.

Respiratory Disorders:

Caution is required if flurbiprofen is administered to patients suffering from, 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).

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.

Caution should be advised in patients receiving concomitant medicinal products that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or platelet anti-aggregators such as acetylsalicylic acid (see section 4.5).

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.

SLE and mixed connective tissue disease:

There may be an increased risk of aseptic meningitis (especially in patients with existing autoimmune disorders such as systemic lupus erythematosus (SLE) and mixed connective tissue disorders) with symptoms of stiff neck, headache, nausea, vomiting, fever or disorientation) (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 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. 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. Flurbiprofen should be used with caution in patients with a potential for abnormal bleeding.

Masking of symptoms of underlying infections:

Epidemiological studies suggest that systemic non-steroidal anti-inflammatory drugs (NSAIDs) can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When flurbiprofen is administered while the patient suffers from fever or pain in relation to infection, monitoring of infection is advised.

Important information regarding the ingredients of Flurbiprofen tablet Sunset yellow: Flurbiprofen tablets contain sunset yellow which may cause allergic reaction.

Sucrose: Flurbiprofen tablets contain sucrose therefore; the patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Glucose: Patients with rare glucose-galactose malabsorption should not take this medicine.

Lactose: Flurbiprofen tablets also contain lactose therefore; patient with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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. Diuretics can also increase the risk of nephrotoxicity of NSAIDs. 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 cardiac 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.

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.

Antiplatelet agents: Increased risk of gastrointestinal bleeding with NSAIDs (see section 4.4)

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

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.

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. From the 20th week of pregnancy onward, flurbiprofen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to flurbiprofen for several days from gestational week 20 onward. Flurbiprofen should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

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

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

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 (see sections 4.3 and 5.3).

Labour and Delivery:

The onset of labour may be delayed and the duration increased with a greater bleeding tendency in both mother and child.

Breast-feeding:

Flurbiprofen is excreted into human breast milk; however, the amount secreted is only a small fraction of the maternal dose. Flurbiprofen is not recommended for use in nursing mothers.

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 breast-feeding.

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 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 4.3 & 4.4) have been reported following flurbiprofen administration. Less frequently, gastritis, has been observed. Pancreatitis has been reported very rarely.

Immune system disorders:

Hypersensitivity reactions have been reported following treatment with Flurbiprofen. 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, erythema multiforme and bullous dermatoses (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

Infections and infestations:

Exacerbation of skin infection-related inflammations (e.g. development of necrotising fasciitis) coinciding with the use of NSAIDs has been described. If signs of an infection occur or get worse during use of flurbiprofen the patient is therefore recommended to go to a doctor without delay.

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).

The following adverse reactions possibly related to flurbiprofen and displayed by MedDRA frequency convention and system organ classification. Frequency groupings are classified according to the subsequent conventions: very common (≥ 1/10), Common (≥ 1/100 to <1/10), Uncommon (≥ 1/1,000 to <1/100), Rare (≥ 1/10,000 to <1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from the available data).

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).

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Symptoms of overdosage may include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning, acidosis, acute renal failure and liver damage are possible. Management

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 patient's clinical condition.

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.

6.1 List of excipients

Sucrose

Lactose

Maize starch

Titanium dioxide

Povidone,

Liquid glucose syrup

Magnesium stearate

Stearic acid

Colloidal silicon dioxide

French chalk for tabletsOpalux ASF 2230 Yellow (contains Sucrose, Quinoline Yellow Al Lake (E 104), Titanium dioxide (E171), sunset yellow FCF Al Lake (E 110), FD & C Yellow No.6, Povidone and Sodium benzoate)

Carnauba wax powder

6.2 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

8 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

02/11/2023