Relifex 500 mg Film-coated Tablets

Each tablet contains 500 mg nabumetone.

For a full list of excipients, see section 6.1.

Dark red, film-coated tablets marked Relifex on one side and "500" on the other.

Nabumetone is a non-acidic non-steroidal anti-inflammatory agent which is a relatively weak inhibitor of prostaglandin synthesis. However, following absorption from the gastrointestinal tract it is rapidly metabolised in the liver to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), a potent inhibitor of prostaglandin synthesis.

It is indicated for the treatment of osteoarthritis and rheumatoid arthritis requiring anti-inflammatory and analgesic treatment.

For oral administration.

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

Relifex 500 mg film-coated tablets should be taken preferably with or after food.

Adults

The recommended daily dose is two tablets (1 g) taken as a single dose at bedtime.

For severe or persistent symptoms, or during acute exacerbations, an additional one or two tablets (500 mg-1 g) may be given as a morning dose.

Elderly

In common with many drugs, blood levels may be higher in elderly patients. The recommended daily dose of two tablets (1 g) should not be exceeded in this age group and in some cases one tablet (500 mg) may give satisfactory relief.

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 patients should be monitored for gastrointestinal bleeding during NSAID therapy.

Children

There are no clinical data to recommend use of Relifex in children.

Hypersensitivity to nabumetone or to any of the excipients.

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

NSAID's 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, hepatic failure and renal failure (see section 4.4).

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

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

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

The use of Relifex with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors should be avoided (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).

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. In patients with impaired renal function (creatinine clearance less than 30 ml/minute), dosage reduction should be considered. Renal function should be monitored in these patients (see also section 4.3).

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 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 (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for nabumetone.

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

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 required 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 received concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anti-coagulants such as warfarin, selective serotonin re-uptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving nabumetone, 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).

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:

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

Impaired female fertility

The use of Relifex 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 Relifex should be considered.

Other analgesics including cyclooxygenase-2 selective inhibitors: avoid the 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 not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

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

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

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 (SSRI's): 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 heamatoma in HIV(+) haemophiliacs receiving concurrent treatment with Zidovudine and ibuprofen.

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 ateriosus), 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 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.

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

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

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

Cardiovascular and cerebrovascular: 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).

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.

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

b) Therapeutic measure: 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 patients clinical condition.

ATC Code: M01AX01

Nabumetone is a non-acidic non-steroidal anti-inflammatory agent which is a relatively weak inhibitor of prostaglandin synthesis. A notable feature of the animal pharmacology is the lack of effect on the gastric mucosa. Following absorption from the gastrointestinal tract nabumetone is rapidly metabolised in the liver to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) a potent inhibitor of prostaglandin synthesis.

Although nabumetone is absorbed essentially intact through the small intestine, extensive metabolism occurs during the first pass through the liver. As a result, concentrations in plasma of nabumetone are barely detectable after oral dosage. Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character. The active metabolite, 6-MNA, binds strongly to plasma proteins; it is distributed into inflamed tissue and crosses the placenta into foetal tissue. It is found in the milk of lactating females. 6-MNA is eliminated by metabolism, principally conjugation with glucuronic acid, and o-demethylation followed by conjugation, the main route of excretion being the urine. The plasma elimination half-life is about 1 day in man.

Not applicable.

Sodium starch glycollate

Sodium lauryl sulphate

Hydroxypropylmethylcellulose (E464)

Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Red carmine (E120)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Talc (E553b)

Polyethylene glycol

Saccharin sodium (E954)

Liquid caramel flavour

Purified water

Carnauba wax (E903)

Not applicable.

36 months.

Keep the tablets in the original carton in order to protect from light.

HDPE bottles each containing 56 tablets.

None.

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd.

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

PL 15142/0106

Date of first Authorisation: 15 March 1984

Date of last Renewal: 14^th March 2007

29^th October 2009