POM: Prescription only medicine
This information is intended for use by health professionals
AdultsThe 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.
ElderlyIn 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.
ChildrenThere are no clinical data to recommend use of Relifex in children.
ElderlyThe 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 severe renal impairment (creatinine clearance less than 30 ml/minute): 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. 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.
Cardiovascular and cerebrovascular effects:Appropriate monitoring and therapy should be instigated if warranted 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 acetylsalicylic acid, aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).Patients with a history of GI peptic disease, particularly when elderly, should report any unusual abdominal symptoms indicative for ulceration (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, NSAIDs, selective serotonin re-uptake inhibitors or anti-platelet agents such as aspirin, acetylsalicylic acid 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 these conditions may be exacerbated (see section 4.8). In patients with active peptic ulcer, physicians must wheigh the benefits of therapy with nabumetone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients' 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:- active upper GI ulceration. Appropriate treatment should be instigated prior to initiating nabumetone therapy.- Previous acetylsalicylic acid, 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.
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 fertilityThe 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.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.
Pregnancy:There is no clinical trial experience with the use of nabumetone during human pregnancy.Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the emryo/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 organogentic 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 prostaglandid 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 unterine contractions resulting in delayed or prolonged labour.Consequently, nabumetone is contraindicated during the third trimester of pregnancy.
Breast feedingThere 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 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.
FertilitySee section 4.4 Special warnings and precautions for use, regarding female fertility.
|Blood and lymphatic system disorders|
|Not known:||Neutropenia, agranulocytosis, leucopenia, aplastic anaemia and haemolytic anaemia.|
|Immune system disorders|
|Very rare:||Anaphylaxis, anaphylactoid reaction|
|Uncommon:||Confusion, nervousness, insomnia|
|Not known:||Depression, hallucinations|
|Nervous system disorders|
|Uncommon:||Somnolence, dizziness, headache, paraesthesia, 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 disorder|
|Not known:||Optic neuritis|
|Ear and labyrinth disorders|
|Common:||Tinnitus, ear disorder|
|Common:||Increases in blood pressure|
|Respiratory, thoracic and mediastinal disorders|
|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, Gl bleeding, gastric ulcer, Gl 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). 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.|
|Very rare:||Hepatic failure, jaundice|
|Skin and subcutaneous tissue disorders|
|Uncommon:||Photosensitivity, urticaria, sweating|
|Very rare:||Bullous reactions induding toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, angioedema, pseudoporphyria, alopecia|
|Musculoskeletal and connective tissue disorders|
|Renal and urinary disorders|
|Uncommon:||Urinary tract disorder|
|Very rare:||Renal failure, nephrotic syndrome|
|Not known:||Interstitial nephritis|
|Reproductive system and breast disorders|
|General disorders and administration site conditions|
|Uncommon:||Elevated liver function tests|
Reporting of suspected adverse reactionsReporting of 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 .
ElderlyThe steady-state plasma concentration in the elderly is usually higher and the half-life longer (29.8±8.1 hours) than in young healthy individuals, but the different intervals overlap to a great extent.
Renal ImpairmentIn patients with severely impaired renal function (creatinine clearance <30 ml/min), the mean value of the half-life of 6-MNA increased to around 40 hours and the plasma levels are 30% higher than in other patients. In patients who underwent dialysis, the steady-state plasma concentration of the active metabolite was equivalent to the values observed in healthy individuals.
Mylan Products Ltd
20 Station Close, Potters Bar, Hertfordshire, EN6 1TL, UK
+44 (0)1707 853000
+44 (0)1707 853 000