Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Fannin (UK) Limited, 42-46 Booth Drive, Park Farm South, Wellingborough, Northamptonshire, NN8 6GT
Hypersensitivity to nabumetone or to any of the other excipients listed in section 6.1
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. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding) or peptic disease.
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.
Patients with current cerebrovascular or other haemorrhage.
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).
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
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.
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/peptic 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, 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 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 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:
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).
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.
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 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). Since peripheral oedema has been observed with nabumetone therapy, the patient should be monitored for exacerbation of the existing condition and appropriate therapy instigated.
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 (see also section 4.3).
In patients with 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).
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.
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.
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.
Since fatal asthma attacks have been reported in such patients receiving other NSAIDs, the first administration of nabumetone should be medically supervised.
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 warranted.
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.
As the major circulating metabolite of Nabumetone 500mg Tablets is highly protein bound, patients receiving concurrent treatment with oral protein-bound anti- coagulants, eg. hydantoin anticonvulsants, sulphonamides or sulphonylurea hyperglycaemics, 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 nephrotoxicity of NSAIDs. Such drugs may also induce hyperkalaemia when administered with potassium- sparing 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.
Hyperkalaemia might develop, particularly with concomitant potassium sparing diuretics administration.
The following commonly available drugs do not affect nabumetone metabolism and bioavailability: paracetamol, ASA, cimetidine, aluminium hydroxide antacids.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels. Use of more than one NSAID is not recommended.
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, such as Zidovudine and Ibuprofen.
Aluminium hydroxide gel, cimetidine, paracetamol and aspirin have not affected the bioavailability of Nabumetone 500mg Tablets in volunteer subjects.
Probenecid: Co-administration reduces the metabolism and elimination of nabumetone.
Alcohol, bisphosphonates, oxpentifylline (pentoxyfilline) and sulfinpyrazone may potentiate GI side-effects and the risk of bleeding or ulceration.
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.
No specific interaction studies with Nambutone and the above have been performed. Caution is therefore recommended for concomitant therapy with the drugs listed above.
There is no clinical trial experience with the use of nabumetone during human 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. In view of the known effects of NSAIDs on the foetus (risk of closure of the ductus ateriosus, pulmonary and cardiac changes), 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.
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:
The mother and the neonate, at the end of pregnancy, to:
Consequently, nabumetone is contraindicated during the third trimester of pregnancy.
There is no clinical trial experience with the use of nabumetone during 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.
6MNA is excreted in the milk of 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.
See section 4.4 – Special warnings and precautions for use, regarding female fertility.
Dizziness, confusion, drowsiness, fatigue, visual disturbances or headaches are possible undesirable effects after taking NSAIDs, if affected, patients should not drive or operate machinery.
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.
Very Rare: Thrombocytopenia
Not known: Neutropenia, agranulocytosis, aplastic anaemia, leucopenia and haemolytic anaemia
Very rare: Anaphylaxis, anaphylactoid reaction
Uncommon: Confusion, nervousness, insomnia
Not known: Depression, hallucinations
Uncommon: Somnolence, dizziness, headache, paresthesia, anxiety
Not known: 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)), vertigo, drowsiness
Uncommon: Abnormal vision, eye disorders
Not known: Optic neuritis
Common: Tinnitus, ear disorder
Common: Increases in blood pressure
Uncommon: Dyspnoea, respiratory disorder, epistaxis
Very rare: Interstitial pneumonitis
Not known: Asthma, aggravated asthma, bronchospasm
Common: Diarrhoea, constipation, dyspepsia, gastritis, nausea, abdominal pain, flatulence
Uncommon: Duodenal ulcer, GI bleeding, gastric ulcer, GI disorder, melaena, vomiting, stomatitis, dry mouth
Very rare: Pancreatitis
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). 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 reported.
Very rare: Hepatic failure, jaundice
Common: Rash, pruritus
Uncommon: Photosensitivity, urticaria, sweating
Very rare: Bullous reactions including toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, angioedema, pseudoporphyria, alopecia
Not known: Purpura
Uncommon: Myopathy
Uncommon: Urinary tract disorder
Very rare: Renal failure, nephrotic syndrome
Not known: Interstitial nephritis
Very rare: Menorrhagia
Common: Oedema
Uncommon: Asthenia, fatigue
Not known: Malaise
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 © 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).
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.
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.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
