- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- Administrative data
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyAdults: The usual starting dose is 1g (two tablets) per day taken as a single daily dose at bedtime.For severe or persistent symptoms, or during acute exacerbations an additional 500mg- 1g may be given as a morning dose.Elderly: Blood levels may be higher in elderly patients because of accumulation of the drug as a result of reduced metabolism and elimination by the liver and kidneys. The recommended daily dose of 1g should not be exceeded in this age group and in some cases 500mg may give satisfactory relief. The risk of serious consequences of adverse effects is increased in the elderly. The lowest dose possible should be used and patients should be monitored for gastrointestinal bleeding for 4 weeks following initiation of therapy with nabumetone.Children: Not recommended as there is no clinical data.
Method of AdministrationFor oral administration. Nabumetone should be administered with or after food to minimise the risk of gastrointestinal adverse effects.Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
ElderlyElderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2)
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 acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and 4.5). Patients with a history of GI peptic disease, particularly when elderly, should be alerted to report any unusual abdominal symptoms indicative for ulceration (especially GI bleeding) particularly in the initial stages of treatment. Caution should be used in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, NSAIDs, SSRIs or anti-platelet agents such as 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 gastro-intestinal disease (Ulcerative colitis, Crohn's disease) as their condition may be exacerbated (see section 4.8). 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 seem low, the prescribing physician should be aware that these ADR can occur even in the absence of previous peptic disease.
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).
Skin reactions: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.
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.
Others:NSAIDs may mask the signs or symptoms of an infection (fever, pain and swelling). 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.
Caution should be used when administering nabumetone to patients with:• Previous acetylsalicylic acid- 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). • 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. • 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 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).
PregnancyThere 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 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.
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, 6-MNA 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|
|Very Rare: Not known:||Thrombocytopenia Anaemia (incl. aplastic anaemia and haemolytic anaemia)|
|Immune system disorders|
|Very rare:||Anaphylaxis, anaphylactoid reaction|
|Uncommon: Not known:||Confusion, nervousness, insomnia Hallucinations|
|Nervous system disorders|
|Uncommon: Not known:||Somnolence, dizziness, headache, paraesthesia 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))|
|Uncommon:||Abnormal vision, eye disorder|
|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|
|Common:||Diarrhoea, constipation, dyspepsia, gastritis, nausea, abdominal pain, flatulence|
|Uncommon:||Duodenal ulcer, GI bleeding, gastric ulcer, GI disorder, melena, vomiting, stomatitis, dry mouth|
|Very rare:||Hepatic failure, jaundice|
|Skin and subcutaneous tissue disorders|
|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|
|Renal and urinary disorders|
|Uncommon:||Urinary tract disorder|
|Very rare:||Renal failure, nephrotic syndrome|
|Reproductive system and breast disorders|
|General disorders and administration site conditions|
|Uncommon:||Elevated liver function tests|
|Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.|
Reporting of suspected adverse reactionsReporting 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; website: www.mhra.gov.uk/yellowcard
Symptoms and SignsThere is no information about overdose. Symptoms include nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness and occasionally convulsions. In cases of significant poisoning, acute renal failure and liver damage are possible.
TreatmentThere is no specific antidote and the active metabolite 6-MNA is not dialysable. Accidental overdose should be treated with gastric lavage followed by activated charcoal and appropriate supportive therapy.
|Oral absorption (%)||≈ 80%|
|Presystemic metabolism to 6-MNA||≈ 100%|
|Normal half life of active metabolite (h) range mean||16-27 hours 22 hours|
|Volume of distribution of 6-MNA (l)||7.5 l.kg-1|
|Plasma protein binding of 6-MNA||≈ 99%|
AbsorptionAlthough 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.
DistributionIntravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character.
Metabolism and eliminationThe active metabolite, 6-MNA, blinds 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 mean plasma elimination half life of 6-MNA is about 22 hours in man.
Actavis UK Ltd
Actavis UK Ltd, a subsidiary of Accord Healthcare Ltd, Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346 106
+44 (0)1271 385 200
+44 (0)1271 385 257