Nabumetone 500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nabumetone 500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Nabumetone 500 mg.
For excipients see 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Brown, capsule-shaped biconvex tablet marked NEO' on one side 'NBU500' on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For use in osteoarthritis and rheumatoid arthritis requiring anti-inflammatory 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 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 1 g should not be exceeded in this age group and in some cases 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 dose should be used and for the shortest duration. The patient should be monitored regularly for gastrointestinal bleeding during NSAID therapy.
Children:
There are no clinical data to recommend use of Nabumetone 500mg Tablets in children.
4.3. Contraindications
Hypersensitivity to nabumetone or any of the other excipients in this medicine.
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.
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
Severe hepatic failure, heart failure and renal failure (see section 4.4.
During the last trimester of pregnancy and in nursing mothers (see section 4.6).
History of 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 500mg Tablets 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 some NSAIDs have been reported to precipitate bronchospasm in such patients.
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 ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, NSAIDs, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin and clopidogrel (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 their condition may be exacerbated (see section 4.8). In patients with active peptic ulcer, physicians must weigh the benefits of therapy with nabumetone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients ‘progress carefully’.
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).
Impaired 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 infertility, withdrawal of nabumetone should be considered.
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 terms treatment) may by 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 eschaemic 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). Since peripheral oedema has been observed with nabumetone therapy, the patient should be monitored for exacerbation of the existing condition and appropriate therapy instigated .
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 clincal 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 years 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): Urine is the major excretion route for the metabolites of Nabumetone Tablets. In patients with impaired renal function, laboratory tests should be performed at baseline and within some weeks of starting therapy. Further tests should be carried out as necessary; if the impairment worsens, discontinuation of therapy may be warranted. It is consistent with good clinical practice that patients with known renal impairment should be monitored regularly during therapy. In moderate renal impairment (creatinine clearance 30 to 49 ml/min) there is a 50% 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 patient should be monitored for exacerbation of the existing condition and appropriate therapy instigated if warrented.
- 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 in the majority of cases within the first month of treatment. Nabumetone should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
- 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.
Liver function: Fluctuations in some parameters of liver function, particularly alkaline phosphatase, are frequently observed in patients with chronic inflammatory disorders; there is no evidence that Nabumetone 500mg Tablets accentuates these changes. However patients with abnormal liver function should be monitored closely and evaluated for evidence of development of a more serious hepatic reaction. Nabumetone should be discontinued if such a reaction occurs.
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).
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 ophtalmological examination.
4.5. Interactions with other medicinal products and other forms of interaction
As the major circulating metabolite of Nabumetone 500mg Tablets is highly protein bound, patients receiving concurrent treatment with oral anti-coagulants, hydantoin anticonvulsants, sulphonamides or sulphonylurea hypoglycaemics should be monitored for signs of overdosage of these drugs. Dosages should be adjusted if necessary.
Other analgesics including cyclooxygenase-2 selective inhibitors: avoid the concomitant use of two or more NSAIDs (including aspirin) as these may increase the risk of adverse effects (see section 4.4).
Anti-hypertensives: reduced antihypertensive effect.
Diuretics:
Reduced diuretic effects. Diuretics can increase the risk of nephrtoxicity of NSAIDs. Such drugs may also induce hyperkalaemia when administered with potassiumsparing diuretics. Interaction studies between Nabumetone 500mg Tablets and these other drugs have not been performed; caution in co-administration is therefore recommended.
Diuretics and other antihypertensives drugs such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists (ARA) may present with decreased effect when concomitantly administered with NSAID; in some persons (such as elderly or dehydrated patients) this could lead to a further decrease in renal function and eventually to ARF. Consequently, hydration and frequent monitoring of these patients is warranted.
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); concomitant administration of anticoagulants with nabumetone should be undertaken with caution and overdose signals carefully monitored.
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 NSAIDs.
Aluminium hydroxide gel, cimetidine, paracetamol and aspirin have not affected the bioavailability of Nabumetone 500mg Tablets in volunteer subjects.
Quinolone antibiotics:
Animal data indicate that some NSAIDs can increase the risk of convulsions associated with quinoline antibiotics. Patients taking NSAIDs and quinolines may have an increased risk of developing convulsions.
4.6. Pregnancy and Lactation
Pregnancy
No teratogenic effects have been demonstrated in experiments with animals. High doses which were maternally toxic were also embryotoxic (rabbit 300mg/kg dose). High doses in rats (320 mg/kg dose) delayed parturition (thought to be due to inhibition of prostaglandin synthesis).
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.
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, nabumetone should not be given unless clearly necessary. If nabumetone 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, nabumetone is contraindicated during the third trimester of pregnancy. Lactation
The active metabolite of nabumetone has been found in the milk of lactating animals. The safety of nabumetone during breastfeeding in humans is not known, use is therefore not recommended.
In limited studies so far available, NSAIDs can appear in 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
Dizziness, confusion, drowsiness, fatigue, visual disturbances or headaches are possible undesirable effects after taking NSAIDs, if affected, patients should not drive or operate machinery.
4.8. Undesirable Effects
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. 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, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia
Immune system disorders
Very rare: Anaphylaxis, anaphylactoid reaction Psychiatric disorders
Uncommon: Confusion, nervousness, insomnia Nervous system disorders
Uncommon: Somnolence, dizziness, headache, paresthesia Eye disorders
Uncommon: Abnormal vision, eye disorders
Ear and labyrinth disorders
Common: Tinnitus, ear disorder
Vascular disorders
Common: Increases in blood pressure
Respiratory, thoracic and mediastinal disorders
Uncommon: Dyspnoea, respiratory disorder, epistaxis
Very rare: Interstitial pneumonitis
Gastrointestinal disorders
Common: Diarrhoea, constipation, dyspepsia, gastritis, nausea, abdominal pain, flatulence
Uncommon: Duodenal ulcer, GI bleeding, gastric ulcer, GI disorder, melena, vomiting, stomatitis, dry mouth
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). , Haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Pancreatitis has been reported very rarely
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 multiforme, angioedema, pseudoporphyria, alopecia
Musculoskeletal and connective tissue disorders
Uncommon: Myopathy Renal and urinary disorders
Uncommon: Urinary tract disorder
Very rare: Renal failure, nephrotic syndrome
Reproductive system and breast disorders
Very rare: Menorrhagia
General disorders and administration site conditions
Common: Oedema Uncommon: Asthenia, fatigue Investigations
Uncommon: Elevated liver function tests
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 type, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necroylsis and erythema multiforme).
Other adverse reactions reported include:
Neurological and special senses: Optic neuritis, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as a stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.
Renal: Nephrotoxicity in various forms, including interstitial nephritis,
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, stroke and death) (see section 4.4).
In clinical trials, increases in doses above 1 g did not lead to an increase in the incidence of side effects. However, the lowest effective dose should always be used.
4.9. Overdose
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
There is no specific antidote and the active metabolite 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 (up to 60g dose given divided doses orally) with appropriate supportive therapy.
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 patient’s clinical condition.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Nabumetone is a non acidic non steroidal anti-inflammatory agent with weak prostaglandin synthesis properties. A notable feature of the animal pharmacology is the lack of effect on the gastric mucosa. Nabumetone is well absorbed from the gastro-intestinal tract and undergoes rapid and extensive metabolism in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), the principal active metabolite which is a potent inhibitor of prostaglandin synthesis.
5.2 Pharmacokinetic properties
Although nabumetone is well absorbed from the GI tract, concentrations in the plasma are too small to be measured as extensive metabolism occurs during the first pass through the liver to the active metabolite 6-methoxy-2-napthylacetic acid (6-MNA) and other inactive metabolites. Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body.
6-MNA is more than 99% bound to plasma protein and diffuses into synovial fluid.
The plasma elimination half-life of 6-MNA varies considerably (mean values reported in young adults of approx. 22 to 27 hours and approx. 25 to 34 hours in the elderly).
6-MNA undergoes further metabolism by 0-methylation and conjugation before being excreted mainly in the urine.
5.3 Preclinical safety data
No data of relevance which is additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch
Sodium Starch Glycollate (Type A)
Povidone
Sodium Lauryl Sulphate Colloidal Silicon Dioxide Magnesium Stearate
Film Coating: Hypromellose Titanium dioxide Talc
Red iron oxide Glycerol triacetate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Blisters of PVC/PVdC/aluminium. Pack sizes of 8, 56 and 100 tablets.
Special precautions for disposal
6.6
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough Northamptonshire NN8 6GT UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20417/0054
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/01/2012
10 DATE OF REVISION OF THE TEXT
13/01/2012