- 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
1. Name of the medicinal product
Nabumetone Tablets 500mg
2. Qualitative and quantitative composition
Each tablet contains 500mg Nabumetone.
3. Pharmaceutical form
Film-coated tabletMaroon, oval, biconvex, film-coated tablets impressed C on one face and the identifying letters NB on the reverse.
4. Clinical particulars
4.1 Therapeutic indications
Nabumetone Tablets are indicated for use in osteoarthritis and rheumatoid arthritis requiring anti-inflammatory and analgesic treatment.
4.2 Posology and method of administration
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).
Nabumetone Tablets should not be given under the following circumstances:• Known hypersensitivity to nabumetone, non-steroidal anti-inflammatory drugs or other ingredients in the tablet. • Patients in whom acetylsalicylic acid or other non-steroidal anti-inflammatory agents precipitate asthmatic attacks, angioedema, urticaria, acute rhinitis or allergic-type reactions. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.• Patients with active peptic ulceration or a history of peptic ulcer disease (2 or more distinct episodes) of recurrent or current GI haemorrhage, perforation or peptic disease.• Patients with a history of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy. • Patients with severe hepatic or renal impairment (eg cirrhosis).• Patients with severe heart failure and in patients with current cerebrovascular or other haemorrhage.• Nabumetone should not be used in patients with uncorrected coagulation defects due to an increase in the risk of gastrointestinal bleeding.• During the last trimester of pregnancy and in nursing mothers (see section 4.6).
4.4 Special warnings and precautions for use
Caution should be taken when prescribing nabumetone in the following circumstances:• Co-administration of nabumetone and other NSAIDs, COX II inhibitors or aspirin increases the risk of adverse effects and such combinations should be avoided.• 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).• ElderlyThe elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).• Gastrointestinal disordersGI 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 previous history of serious GI events. When GI bleeding or ulceration occurs in patients receiving nabumetone the treatment should be withdrawn. 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 at the lowest dose available.Combination therapy with protective agents (e.g. misoprolol 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 toxicity, particularly the 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 corticoseroids, anticoagulants such as warfarin or anti-platelet agents such as aspirin and clopidogrel (see section 4.5).Nabumetone should be used with caution in 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 weigh the benefits of therapy with nabumetone against possible hazards, institute an appropriate ulcer treatmetnregimen 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 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 ADRs can occur even in the absence of previous peptic disease.When GI bleeding or ulceration occurs in patients receiving Nabumetone, the treatment should be withdrawn.• Cardiovascular and cerebrovascular effectsAppropriate 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).• Administration of nabumetone can lower serum thyroid hormone levels and can affect the interpretation of thyroid function tests.• Impaired female fertilityThe 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.• 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.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 ).• fluid retention, hypotension, a history of hypertension and/or heart failure. Fluid retention and peripheral oedema have been reported in association with NSAID therapy and the patients should be monitored for exacerbation of the excisting condition and appropriate therapy instigated if warranted. • 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. Additionally, nabumetone should be used with caution in patients suffering from or with a history of asthma as NSAIDs have been reported to precipitate broncospasm in such patients.• severe renal impairment (creatinine clearance less than 30ml/min) should have laboratory tests performed at base line and within some weeks of starting therapy. If the impairment worsens discontinuation of therapy may be warranted, as the renal route is the major excretion route for the metabolites of nabumetone. In patients with moderate renal function impairment (creatinine clearance 30 to 49ml/min) there is a 50% increase in unbound plasma 6-MNA and dosage reduction should be considered (see section 4.5).• 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.• infections as it may mask symptoms such as fever and inflammation.• systemic lupus erythromatosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).• serious skin reactions, some of them fatal, including exfoilative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see 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 months of treatment. Nabumetone should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
4.5 Interaction with other medicinal products and other forms of interaction
Caution should be taken if concurrent administration of any of the following drugs or groups of drugs is indicated.• ACE inhibitors and angiotensin II receptor antagonistsCo-administration of NSAIDs and ACE inhibitors and angiotensin II receptor antagonists is associated with an increased risk of renal impairment due to decreased renal perfusion. Prostaglandins may be involved in the antihypertensive effects of these drugs and inhibition of prostaglandin synthetase by NSAIDs may antagonise these effects. The risk of hyperkalaemia may be increased in patients taking ACE inhibitors or angiotensin II receptor antagonists with NSAIDs. 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.• Adrenergic neurone blockersNSAIDs may antagonise the hypotensive effects of adrenergic neurone blockers.• AlcoholAlcohol may increase the risk of gastrointestinal bleeding and ulceration in patients taking NSAIDs.• AnalgesicsConcurrent administration of nabumetone with other NSAIDs, including aspirin, is contraindicated because of the risk of additive adverse effects on the gastrointestinal tract (see section 4.3). • AntibacterialsIsolated reports of convulsions or other neurological toxicity and skin eruptions have been noted in patients taking NSAIDs when quinolones are added to their therapy. The risk appears to be small but concurrent use should be monitored carefully in epileptic patients. Decreased renal clearance with correspondingly increased toxicity has been observed in patients taking NSAIDs and aminoglycosides concurrently.• AnticoagulantsThe effects of coumarins, phenindione and heparins may be enhanced by concurrent administration with NSAIDs. The combination should be used with care as NSAIDs have an effect on platelet activity and can affect bleeding times. NSAIDs also increase the risk of gastrointestinal bleeding and ulceration in patients taking anticoagulants. Nabumetone specifically does not usually interact with warfarin or acenocoumarol but isolated cases of increases in INR and haemarthrosis have been noted so concurrent use should be monitored carefully.• AntidepressantsThe risk of bleeding may be increased when NSAIDs are administered concurrently with SSRIs, venlafaxine or moclobemide.• AntidiabeticsNSAIDs such as nabumetone which are highly protein bound can displace sulphonylureas from binding sites with a corresponding increase in hypoglycaemic activity. Rosiglitazone can cause fluid retention which can exacerbate or precipitate heart failure. • AntiepilepticsNSAIDs such as nabumetone which are highly protein bound can displace phenytoin from binding sites with a corresponding increase in the risk of phenytoin toxicity.• AntiviralsPlasma levels of NSAIDs may be increased in patients taking ritonavir. The risk of haematological toxicity may be increased when NSAIDs are co-administered with zidovudine and blood counts are recommended for 1 to 2 weeks after starting concurrent therapy.• Beta blockersCo-administration of NSAIDs with beta blockers can result in an antagonism of antihypertensive activity. This is due to an increased risk of renal impairment due to decreased renal perfusion. Prostaglandins may be involved in the antihypertensive effects of beta blockers and inhibition of prostaglandin synthetase by NSAIDs may antagonise this activity.• BisphosphonatesThe risks of oesophagitis and gastrointestinal bleeding and ulceration are increased by concomitant administration of NSAIDs and bisphosphonates and co-administration should be avoided.• Calcium channel blockersThe antihypertensive activity of calcium channel blockers may be antagonised by NSAIDs.• Cardiac glycosidesPlasma levels of digoxin may be increased in patients taking NSAIDs with a corresponding increase in the risk of toxicity. NSAIDs may exacerbate the decline in renal function in susceptible patients, such as the elderly, leading to an increased risk of heart failure.• ClonidineThe antihypertensive effects of clonidine may be antagonised by concurrent administration of NSAIDs.• ClopidrogelThe risk of gastrointestinal bleeding is increased by concomitant administration of NSAIDs and clopidrogel.• CorticosteroidsThe risk of gastrointestinal bleeding and ulceration is increased by concomitant administration of NSAIDs and corticosteroids.• CytotoxicsConcomitant use of NSAIDs and methotrexate should be monitored closely, especially in patients with compromised renal function. NSAIDs inhibit renal perfusion as a result of their effects on prostaglandin synthetase. This results in a reduction in the renal excretion of methotrexate with a corresponding increase in the risk of methotrexate toxicity. In addition, highly protein bound NSAIDs may displace methotrexate from protein binding sites to enhance the risk of methotrexate toxicity. • DiureticsThere is a reduced diuretic effect. The antihypertensive effects of diuretics are antagonised by concomitant administration with NSAIDs due to the effects of NSAIDs on prostaglandin synthetase activity in the kidney. The risk of adverse effects is greatest in patients with cirrhosis, cardiac failure and/or renal insufficiency. The risk of hyperkalaemia may be increased in patients taking potassium sparing diuretics and NSAIDs concomitantly because of the effects of NSAIDs on renal function. • ImmunosuppressantsThe risk of nephrotoxicity is increased when ciclosporin and NSAIDs are administered concomitantly. The inhibition of prostaglandin synthetase by NSAIDs in the kidney may result in a reduction of glomerular filtration rate and renal blood flow required to protect the kidney from the nephrotoxic effects of ciclosporin. Similar effects may be observed in patients taking tacrolimus and NSAIDs concurrently.• LithiumThe inhibition of renal prostaglandins by NSAIDs reduces renal blood flow. This reduces the renal excretion of lithium with a resultant increase in plasma levels and an increased risk of lithium toxicity. Concomitant administration of lithium and NSAIDs should be monitored carefully and avoided whenever possible.• MethyldopaThe antihypertensive effects of methyldopa may be antagonised by concurrent administration of NSAIDs.• MifepristoneThere is a theoretical risk that NSAIDs will reduce the efficacy of mifepristone because of their inhibitory effects on prostaglandin synthetase and it is recommended that administration of NSAIDs should be avoided for 8 to 12 days after the use of mifepristone.• Muscle relaxantsThe renal excretion of baclofen may be inhibited when it is co-administered with NSAIDs with a possible increase in the risk of toxicity.• NitratesThe hypotensive effects of nitrates may be antagonised by concurrent administration of NSAIDs.• PentoxifyllineThe risk of gastrointestinal bleeding and ulceration may be increased by concomitant administration of NSAIDs and pentoxifylline.• ProgestogensThe risk of hyperkalaemia may be increased by concomitant administration of drospirenone with NSAIDs and serum potassium should be monitored during the first treatment cycle.• SibutramineThe risk of gastrointestinal bleeding is enhanced when NSAIDs are administered concomitantly with sibutramine.• VasodilatorsCo-administration of NSAIDs with hydralazine, minoxidil or nitroprusside can result in antagonism of hypotensive activity. This is due to an increased risk of renal impairment due to decreased renal perfusion. Prostaglandins may be involved in the hypotensive effects of these vasodilators and inhibition of prostaglandin synthetase by NSAIDs may antagonise this activity.The following commonly available drugs do not affect nabumetone metabolism and bioavailability: paracetamol, cimetidine and aluminium hydroxide antacids.Concomitant administration of nabumetone with other protein-bound drugs, e.g. sulphonamides and hydantoin should be undertaken with caution and overdose signals carefully monitored.
4.6 Pregnancy and lactation
PregnancySafety of nabumetone in human pregnancy has not been established.Use of NSAIDs in women prior to conception may lead to an increased risk of miscarriage. Until further studies verify the risks to the unborn child, women of childbearing age planning pregnancy should be advised to avoid taking nabumetone when trying to conceive a child. The investigators thought that this was due to the inhibitory effects of NSAIDs on prostaglandin synthetase. Prostaglandins are necessary for successful implantation into the uterine wall and are also involved in the ovulation process. It would be prudent to advise women hoping to conceive to take an alternative analgesic, such as paracetamol. NSAIDs are also associated with an increased risk of spontaneous abortion.Use of NSAIDs during the first and second trimester of pregnancy should be avoided because of possible adverse effects on the fetus, such as congenital abnormalities such as premature closure of the ductus arteriosus, which may lead to pulmonary hypertension in the newborn these are low in frequency and do not appear to follow any discernible pattern. NSAIDs have been associated with a delayed onset and increased duration of labour 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 patients outweighs the potential risk to the foetus.Use of nabumetone is contraindicated in the third trimester of pregnancy. The known effects of NSAIDs on the human foetus during the third trimester of pregnancy include adverse effects such as premature closure of the ductus arteriosus, which may lead to pulmonary hypertension in the newborn, and pulmonary and cardiac changes. These are low in frequency and do not appear to follow any discernible pattern.
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.See section 4.4 for information on female fertility.
4.7 Effects on ability to drive and use machines
As nabumetone can cause visual disturbances, drowsiness, dizziness, confusion and headache, patients should make sure they are not affected before driving or operating machinery.
4.8 Undesirable effects
In clinical trials increases in dose above 1g did not lead to an increase in the incidence of side effects. However, the lowest effective dose should always be used.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 disordersVery rare: Blood dyscrasias including leucopenia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.• Immune system disordersVery rare: anaphylaxis and anaphylactoid reactions.Skin reactions may be urticarial, macropapular, vesicular or exfoliative. Pruritus, rash, urticaria, photosensitivity reactions including pseudoporphyria, severe skin eruptions (eg Stevens Johnson syndrome), erythema multiforme and toxic epidermal necrolysis have been reported very rarely. They are probably of phototoxic origin and may be associated with systemic hypersensitivity or other allergic reaction. Skin pigmentation and environmental factors also determine the risk of phototoxic reactions. Serious allergic reactions involving the skin may have a genetic component. Non-specific allergic reactions, including vasomotor rhinitis, angioedema, bronchospasm, asthma and dyspnoea have been reported. Alveolitis and pulmonary eosinophilia have been reported rarely as an allergic response to NSAIDs. Pancreatitis has been reported. Reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus or mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4).• Psychiatric disordersUncommon: Confusion, nervousness, insomnia.Depression and hallucinations have been reported.• Nervous system disordersUncommon: Headache, dizziness, paraesthesia, somnolence.Sedation, fatigue, vertigo, drowsiness and malaise have been reported. • Eye disordersUncommon: Abnormal vision, eye disorders (optic neuritis, ocular discomfort and irritation, papilloedema and optic or retrobulbar neuritis).• Ear and labyrinth disordersCommon: Tinnitus, ear disorders.• Cardiac disordersOedema. Heart failure has been reported in elderly patients. Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.• Respiratory, thoracic and mediastinal disordersUncommon: Dyspnoea, respiratory disorder, epistaxis.Very rare: Intersitial pneumonitis.• Gastrointestinal disordersThe most commonly observed adverse effects associated with NSAID administration are gastrointestinal in nature. All NSAIDs can cause damage to the gastrointestinal mucosa. Gastrointestinal adverse effects are due to central activities of NSAIDs as well as local effects on the mucosa. Risk factors are age, history of ulcers and/or gastrointestinal bleeding, use of NSAIDs in combination with corticosteroids or with other NSAIDs. Sex (female), the musculoskeletal disease being treated and the NSAID taken and dosage used also affect the risk of developing gastrointestinal adverse effects. Treatment with NSAIDs should begin with a low dose. Common: Diarrhoea, constipation, dyspepsia, gastritis, nausea, abdominal pain, flatulence.Uncommon: Dry mouth, stomatitis, vomiting, melaena, haematemesis gastrointestinal ulceration, bleeding or perforation.Induction or exacerbation of colitis and Crohn's disease and erosive and/or ulcerative oesophagitis, ulceration of the oesophagus with or without bleeding and/or oesophageal perforation or strictures have been reported in patients taking NSAIDs, usually as long term therapy.Severe intestinal bleeding and perforation are very rare complications of long term therapy with NSAIDs. Perforation can lead to peritonitis and death.• Hepato-biliary disordersVery rare: Hepatic failure, jaundice. NSAIDs are also associated with hepatitis.• Skin and subcutaneous tissue disordersCommon: Rash, pruritus.Uncommon: Photosensitivity, urticaria (sometimes associated with angioedema), sweating.Very rare: Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia, pseudoporphyria, erythema multiforme, angioedema.NSAIDs can exacerbate pre-existing skin diseases, such as acne and psoriasis, on rare occasions.• Musculoskeletal and connective tissue disordersUncommon: myopathy.• Renal and urinary disordersAll NSAIDs have the potential to cause nephrotoxicity. This results from haemodynamic changes that occur secondary to the inhibition of prostaglandin synthetase in the kidney. Patients at particular risk include those with pre-existing renal impairment and hypertensive renal disease who require long term treatment with NSAIDs. NSAIDs with long half lives, such as nabumetone, are associated with a greater potential to cause nephrotoxicity.Uncommon: Urinary tract disorder.Very rare: Renal failure, acute interstitial nephritis, distinguished by a nephrotic syndrome that is often accompanied by renal insufficiency, has been reported in patients on long term therapy with NSAIDs.Functional renal insufficiency is the most common adverse effect of NSAIDs on the renal system. It is usually mild and reversible within a few days of withdrawing NSAID therapy. Renal papillary necrosis has also been reported in patients on long term NSAID therapy. Haematuria has been reported.• Reproductive system and breast disordersVery rare: MenorrhagiaNSAIDs can affect fertility in women hoping to conceive (see section 4.6). • General disorders and administrative site conditionsCommon: OedemaUncommon: Asthenia, fatigue.• InvestigationsUncommon: Elevated liver function tests.Clinical trial and epidemiological data suggests 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 or stroke (see section 4.4).
Symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.There is no specific antidote and the active metabolite 6-MNA is not dialysable. Treatment: 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. 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.
5. Pharmacological properties
5.1 Pharmacodynamic properties
ATC code M01A X01.Nabumetone is a non-acidic NSAID which is a relatively weak inhibitor of prostaglandin synthesis. Following absorption from the gastrointestinal tract nabumetone is rapidly metabolised in the liver to the principal active metabolite, 6-methoxy-2-naphylacetic acid (6-MNA) a potent inhibitor of prostaglandin synthesis. Nabumetone is a naproxen derivative and 6-MNA is structurally similar to naproxen.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of nabumetone are summarised in the table below:
|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.
5.3 Preclinical safety data
No mutagenic activity was demonstrated in the Ames test or the mouse micronucleus test in vivo. However, chromosomal aberrations occurred in lymphocytes exposed in vitro to nabumetone or its active metabolite 6-MNA at concentrations of 80μg/ml or higher. Nabumetone produced no carcinogenic effects in rats or mice in life time studies.No teratogenic potential has been demonstrated in experiments with animals. High doses (rabbit, 300mg/kg) which were maternally toxic were also embryotoxic. High doses in rats (320mg/kg) delayed parturition (probably due to an inhibition of prostaglandin synthesis).The active metabolite of nabumetone 6-MNA is distributed into milk of lactating rats in concentrations approximately equal to those in plasma.
6. Pharmaceutical particulars
6.1 List of excipients
The tablets also contain: microcrystalline cellulose 101 (E460), hydroxypropylmethylcellulose (E464), sodium lauryl sulphate, sodium starch glycollate, colloidal silica, magnesium stearate.The coating contains: hydroxypropylmethylcellulose (E464), propylene glycol, purified talc (E553), carmoisine aluminium lake (E122), indigo carmine aluminium lake (E132), titanium dioxide (E171).
6.3 Shelf life
Three years from the date of manufacture.
6.4 Special precautions for storage
Store in the original container.
6.5 Nature and contents of container
The blister packs are manufactured from 250µm white rigid PVC and 20µm hard temper aluminium foil. The polypropylene containers are manufactured from rigid injection moulded polypropylene with snap-on polyethylene lids.Pack sizes: 28s, 56s, 84s, 112s (blisters)
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
Actavis UK Limited (Trading style: Actavis)Whiddon ValleyBARNSTAPLEN Devon EX32 8NS
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
1 November 1999Renewed 10/03/2009
10. Date of revision of the text
Actavis UK Ltd
Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346 106
Medical Information e-mail
+44 (0)1271 311 200
Medical Information Direct Line
+44 (0)1271 311 257