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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nabumetone 500mg Tablets BP.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Nabumetone 500mg.

3.    PHARMACEUTICAL FORM

Film coated tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the treatment of osteoarthritis and rheumatoid arthritis requiring antiinflammatory and analgesic treatment.

4.2    Posology and method of administration

For oral administration. To be taken preferably with or after food.

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

Adults The recommended daily dose is 1g (two tablets) taken as a single dose in the evening. For severe or persistent symptoms, or during acute exacerbations, an additional one to two

tablets (500mg-1g) may be given in the morning. Elderly Blood levels may be higher in elderly patients. The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary the lowest dose should be used and the patient should be monitored for gastrointestinal bleeding for 4 weeks following initiation of nabumetone therapy.

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.

The recommended daily dose of 1g should not be exceeded in this age group, and in many cases 500mg should be satisfactory. Children There is no clinical evidence to recommend use of Nabumetone in children.

4.3 Contraindications

Nabumetone film-coated, dispersible and chewable tablets, sachet and suspension are contraindicated in patients with previous history of hypersensitivity to nabumetone or excipients (see section 6.1).

Nabumetone must not be given to patients who have experienced asthma, urticaria, rhinitis, angioedema or allergic-type reactions after taking aspirin, ibuprofen or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.

Nabumetone is contraindicated in patients with severe hepatic failure.

Nabumetone is contraindicated in patients with severe renal failure.

Nabumetone is contraindicated in patients with previous history (2 or more distinct episodes) of recurrent or current GI haemorrhage, perforation or peptic disease, ulcer.

Nabumetone is contraindicated in the third trimester of pregnancy and in nursing mothers.

Nabumethone is contraindicated in patients with severe heart failure, and in patients with current cerebrovascular or other haemorrhage.

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

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).

The use of nabumetone 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 dependant 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).

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 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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin, NSAIDs, SSRIs or anti-platelet agents such as aspirin and clopidrogel (see section 4.5 Interactions). In patients with active peptic ulcer, physicians must weigh the benefits of therapy with nabutemone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patient’s progress carefully.

Nabumetone is better tolerated than most other NSAIDs, primarily because it results in fewer effects on the gastrointestinal (GI) system. In a review of both pre-and post registration data from clinical trials with Nabumetone, the mean cumulative frequencies of GI perforations, ulcers or bleeds (PUBs) in patients treated from 3 to 6 months, 1 year and 2 year were respectively 0.3%, 0.5% and 0.8%; although these figures are lower than those ascribed to other NSAIDs, the prescribing physician should be aware that these ADR can occur even in the absence of previous peptic disease.

Despite the relative gastrointestinal and renal safety of nabumetone, caution should be used when administering to patients with:

•    active upper GI ulceration. Appropriate treatment should be instigated prior to initiating Nabumetone therapy.

•    history of upper GI ulceration. The patient should be alerted to report symptoms indicative of ulceration

•    other therapies known to increase the risk of gastrointestinal ulcer (e.g. oral corticosteroids).

•    severe renal impairment (creatinine clearance less than 30 ml/min): laboratory tests should be performed at baseline and within some weeks of starting therapy. Further tests should be carried out necessary; if the impairment (creatinine clearance 30 to 49 ml/min) there is a 59% increase in unbound plasma 6-MNA and dose reduction may be warranted (see section 4.5).

•    previous aspirin or other NSAID-induced asthma, urticaria or other allergic type reactions. Since fatal asthma attacks have been reported in such patients receiving other NSAIDs, the first administration of Nabumetone should be medically supervised.

•    fluid retention, hypertension and/ or heart failure. Since peripheral oedema has been observed with Nabumetone therapy, the patients should be monitored for exacerbation of the existing condition and appropriate therapy instigated if warranted.

•    severe hepatic impairment. As with other NSAIDs, abnormalities of liver function tests, rare cases of jaundice and hepatic failure (some of them with fatal outcomes), have been reported. A patient with signs/ symptoms suggesting liver dysfunction or who has experienced an abnormal liver function test while on nabumetone therapy should be evaluated for evidence of development of a more serious hepatic reaction. Nabumetone should be discontinued if such a reaction occurs.

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 diseases (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).

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 the therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac should be discontinued at the first appearance of skin risk, mucosal lesions, or any other sign of hypersensitivity.

Female fertility:

The use of nabumetone 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 fertility, withdrawal of nabumetone should be considered.

NSAIDs could hide signs of infectious disease.

Cases of blurred vision or reduced visual activity have been reported with NSAID use, including Nabumetone. Patients presenting with these events must be submitted to ophthalmological examination.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Concurrent administration with other plasma protein binding drugs may necessitate a modification of the dosage.

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 lithium.

Methotrexate: Decreased elimination of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

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 and other anticoagulants (See section 4.4); its concomitant administration with nabumetone should be undertaken with caution and overdose signals carefully monitored.

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

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);

Increase risk of gastrointestinal bleeding (see section 4.4)

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine:

Increased risk of hematological 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.

The following commonly available drugs do not affect nabumetone metabolism and bioavailability: paracetamol, ASA, cimetidine, aluminium hydroxide antacids.

Hyperkalaemia might develop, particularly with concomitant potassium-sparing diuretics administration.

Diuretics and other anti-hypertensive drugs such as angiotensin receptor antagonists (ARA) may present with decreased effect when concomitantly administered with NSAIDs, in some persons ( such as elderly or dehydrated patients) this could lead to a further decrease in renal functions and eventually to ARF. Consequently, hydration and frequent monitoring of these patients is warranted.

Concomitant administration of nabumetone with other protein-bound drugs, e.g. sulphonamides, sulphonylureas or hydantoin should be undertaken with caution, overdose signals carefully monitored.

No specific interaction studies between nabumetone and the above have been performed. Caution is therefore recommended for concomitant therapy with the drugs listed above.

4.6 Pregnancy and lactation

Pregnancy

There is no clinical trial experience with the use of nabumetone during human 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 the mother and the child (See section 4.3 -Contraindications). NSAIDs should not be used during the first two trimester of the 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 concentrates. NSAIDs should, if possible, be avoided when breastfeeding. See section 4.4 - Special warning and precautions for use, regarding female fertility.

There is no clinical trial experience with the use of Nabumetone during lactation. It is not known whether nabumetone is excreted in human milk, however, 6MNA is excreted in the milk lactating rats. With the potential for serious adverse reactions in breast fed infants from nabumetone, a decision should be made whether to discontinue breast feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

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

The frequencies of adverse events are ranked according to the following: very common (>1/10), common (>1/100 to < 1/10), uncommon (>1/1000 to < 1/100), rare (>1/10000 to < 1/1000), very rare (>1/10000; including isolated reports), not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo and comparator groups has not been taken into account in estimation of these frequencies. Rare and very rare events were generally determined from spontaneous data.

Blood and lymphatic system disorders Very rare Thrombocytopenia

Not Known Neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia. Immune system disorders

Very rare Anaphylaxis, anaphylactoid reaction Psychiatric disorders

Uncommon: Confusion, nervousness, insomnia Not known: Depression, hallucination

Nervous system disorders

Uncommon Somnolence, dizziness, headache, paresthesia Eye disorders

Uncommon Abnormal vision, eye disorder

Ear and labyrinth disorders Common Tinnitus, ear disorders

Vascular disorders

Common    Increase in blood pressure

Respiratory, thoracic and mediastinal disorders Uncommon    Dyspnoea, respiratory disorder, epistaxis

Very rare    Interstinal pneumonitis

Gastrointestinal disorders

Common    Diarrhoea, constipation, dyspepsia,    nausea, abdominal pain, flatulence

Uncommon Duodenal ulcer, gastrointestinal haemorrhage, gastric ulcer, GI disorders, melaena, vomiting, stomatitis, dry mouth.

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) have been reported following administration. Less frequently, gastritis has been observed.

Hepatobiliary disorders

Very rare    Hepatic failure, jaundice

Skin and subcutaneous tissue disorders

Common    Rash, pruritus

Uncommon Photosensitivity, urticaria, sweating

Very rare Bullous reactions including toxic epidermal necrolysis, stevens Johnson syndrome,

Erythema multifrome, angioedema, pseudoporphyria, alopecia Not Known Purpura

Musculoskeletal and connective tissue disorders Uncommon: Myopathy

Renal and urinary disorders Uncommon    Urinary tract disorders

Very rare    Renal failure, nephrotic syndrome

Not Known Renal impairment, nephertis interstitial

Reproductive system and breast disorders Very rare    Menorrhagia

General disorders and administration site conditions Common    Oedema

Uncommon Asthenia, fatigue

Investigations

Uncommmon Elevated liver function tests

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 infraction, stroke and death) (see

section 4.4)

4.9 Overdose

a)    Symptoms and signs

There is no information about overdose.

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

b)    Treatment

There is no specific antidote and the active metabolite 6-MNA is not dialyzable. 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 closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequently 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

Nabumetone is a non acidic non steroidal anti-inflammatory agent which is a relatively weak inhibitor of prostaglandin synthesis. A notable characteristic of the animal pharmacology is the lack of pH effect on the gastric mucosa. Nabumetone is a pro-drug. Following absorption from the gastro-intestinal tract, it undergoes metabolism in the liver to the major active metabolite, 6-methoxy-2-naphyhylacetic acid (6-MNA), a potent inhibitor of prostaglandin synthesis.

5.2. Pharmacokinetic Properties

Although Nabumetone is absorbed essentially intact via the small intestine, majority of first pass metabolism occurs in the liver. Consequently, plasma concentrations of Nabumetone are barely detectable after oral administration. Intravenous studies in rats with Nabumetone indicate it to be rapidly distributed throughout the body. 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, mainly by 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.

5.3. Preclinical Safety Data

There are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Maize Starch

Sodium Starch Glycollate

Povidone K30

Water

Microcrystalline Cellulose (PH102)

Magnesium Stearate

Opadry- LS-26411 (maroon) contains : hydroxypropylmethylcellulose Lactose Monohydrate PEG 4000

Carmoisine Lake (E122),

Titanium Dioxide (E171),

Caramel Flavouring,

Talc,

Saccharin Sodium,

FD&C Blue #2/Indigo Carmine Lake (E132)

6.2. Incompatibilities

None

22 September 2000

DATE OF REVISION OF THE TEXT

29/11/2010