Nabumetone 500mg Film-Coated Tablet
Nabumetone 500mg Film-Coated Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 500 mg nabumetone.
Each film-coated tablet also contains sunset yellow (E110) and ponceau 4R (E124). For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
The film-coated tablets are pink/red biconvex capsule shaped film-coated tablets, debossed with NB500 on one side and G on the other.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Nabumetone is indicated in the symptomatic treatment of osteoarthritis, both acute and chronic, and rheumatoid arthritis, both acute and chronic requiring anti-inflammatory and analgesic treatment.
4.2 Posology and method of administration
Treatment should be reviewed at regular intervals and discontinued if a benefit is not observed or intolerance occurs.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
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.
Paediatric population :
There are limited clinical data in the paediatric population. The safety and efficacy of nabumetone in children under the age of 18 has not been established.
Older people :
Blood levels may be higher in older people; therefore NSAIDs should be used with particular caution in this group as older patients are more prone to adverse events. Older people present higher rates of nonsteroidal anti-inflammatory drugs (NSAIDs) related adverse drug reactions (ADR), particularly gastrointestinal (GI) haemorrhage and perforation that can potentially be fatal.
It is advised to begin treatment with 500 mg per day, which, in most cases, provides a sufficient relief; total daily dosage should not exceed 1 g/day. The lowest dose compatible with adequate safe clinical control should be employed and for the shortest possible duration. The patients should be monitored for gastrointestinal bleeding during NSAID therapy (see section 4.4).
Patients with renal impairment
In moderate renal impairment (creatinine clearance 30 to 49 ml/min) there is a 50 % increase in unbound plasma 6-methoxy-2-naphthylacetic acid (6-MNA) and dose reduction may be warranted (see section 4.4 for severe impairment and advice on monitoring, and section 4.5).
Patients with hepatic impairment
Available information is limited to single-dose studies. No dosage adjustment should be necessary in patients with mild or moderate hepatic impairment (see section 4.4 for severe impairment and advice on monitoring).
Method of administration For oral use.
Nabumetone should be taken preferably with or after food.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Nabumetone must not be given to patients who have experienced asthma, urticaria, or allergictype reactions after taking acetylsalicyclic acid, or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Nabumetone is contraindicated in patients with severe hepatic failure.
Nabumetone is contraindicated in patients with previous history (2 or more distinct episodes) of recurrent or current GI haemorrhage, perforation or peptic ulceration.
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Nabumetone is contraindicated in the third trimester of pregnancy and in nursing mothers (see section 4.6).
Nabumetone is contraindicated in patients with severe heart failure, and renal failure (creatinine clearance < 30 ml/min) and in patients with current cerebrovascular or other haemorrhage (see section 4.4).
The use of nabumetone with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms (see section 4.2 and GI and cardiovascular risks below).
Patients on long term treatment should be reviewed at regular intervals. Nabumetone should be discontinued if no clinical benefit is seen or risk-benefit is no longer favourable.
Older people :
Older people have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). If an NSAID is considered necessary, the lowest effective dose should be used and the patient should be monitored for gastrointestinal bleeding.
Gastrointestinal bleeding, ulceration and perforation:
Gastrointestinal 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 older people. 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 4.5). Patients with a history of GI peptic disease, particularly when older, 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, SSRIs or anti-platelet agents such as acetylsalicylic acid (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 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 treatment regimen and monitor the patients’ progress carefully.
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).
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.
• 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 30ml/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).
• 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 warranted.
• 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.
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.
NSAIDs could hide signs of infectious disease (fever, pain and swelling).
Cases of blurred vision or reduced visual activity have been reported with NSAID use, including nabumetone. If a patient reports loss of vision or blurred vision, an eye examination should be performed.
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 older people. Renal function should be monitored in these patients (see also section 4.3).
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).
Excipient warning (Allergic type reactions):
Nabumetone contains the colourants sunset yellow (E110) and ponceau 4R (E124) which may cause allergic reactions.
Nabumetone has been shown to interact with the pharmacokinetic and pharmacodynamic characteristics of a number of drugs leading to potential adverse effects. Care should be taken in patients treated with any of the following:
Corticosteroids: There is increased risk of gastrointestinal ulceration or bleeding when corticosteroids are taken with NSAIDs (see section 4.4).
Anticoagulants: NSAIDs may enhance the effect of anticoagulant drugs with increased risk of bleeding. Concomitant use of warfarin, heparin, or other anticoagulants is not advised unless under direct medical supervision and overdose signals carefully monitored (see section 4.4).
Antiplatelet 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 zidovudine and ibuprofen
Other analgesics including cyclooxygenase-2 selective inhibitors: avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.3).
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 older people 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. There is a possible risk of hyperkalaemia, particularly when potassium sparing diuretics are used concomitantly with nabumetone.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: Decreased elimination of lithium occurs when NSAIDs are co-administered and lithium toxicity may be precipitated.
Methotrexate: A number of NSAIDs have been shown to increase plasma levels of methotrexate (associated with decreased renal elimination of methotrexate and possibly competition for plasma protein binding sites) and so may induce methotrexate toxicity.
Ciclosporin: NSAIDs increase the risk of nephrotoxicity with this drug.
Aminoglycosides: Concomitant administration of aminoglycosides may lead to a reduction in renal function in susceptible individuals, decreased elimination of aminoglycosides and increased plasma concentrations in susceptible individuals.
Mifepristone: NSAIDs should not be used for 8 - 12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Probenecid: Reduction in the metabolism of nabumetone and a reduction in the elimination of nabumetone and metabolites.
Oral hypoglycaemic agents: Inhibition of metabolism of sulfonylurea drugs, prolonged half life and increased risk of hypoglycaemia.
Quinolone antibiotics: Animal data indicate that NSAIDs increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Alcohol, bisphosphonates, oxpentifylline (pentoxyfilline) and sulfinpyrazone: May potentiate the GI side effects and the risk of bleeding or ulceration.
As the major circulating metabolite of nabumetone is highly plasma bound, patients receiving other protein bound drugs e.g. sulfonamides, hydantoin anti-convulsants, oral anticoagulants and sulfonylureas should be monitored for signs of overdose. Dosages should be adjusted if necessary.
The following commonly available drugs do not affect nabumetone metabolism and bioavailability: paracetamol, cimetidine, aluminium hydroxide antacids.
No specific interaction studies between nabumetone 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.
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.
There 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-methoxy-2-naphthylacetic acid (6MNA) is excreted in the milk of lactating rats. With the potential for serious adverse reactions in breastfed 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, regarding female fertility.
Dizziness and confusion have been reported after administration of nabumetone. Other undesirable effects such as drowsiness, fatigue and visual disturbances are possible 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 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000) and very rare (<1/10,000), not known (frequency cannot be estimated from available data). 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.
Not known: Meningitis aseptic (especially in patients with existing autoimmune disorders,
such as systemic lupus erythematosus, mixed connective tissue disorder), with symptoms such as stiff neck, headache, nausea, vomiting, fever and disorientation (see section 4.4)
Blood and lymphatic system disorders Very rare: Thrombocytopenia
Not known: Neutropenia, agranulocytosis, leukopenia, anaemia (incl. aplastic anaemia,
and haemolytic anaemia)
Immune system disorders
Very rare: Anaphylaxis, anaphylactoid reaction
Hypersensitivity reactions have been reported following treatment with NSAIDs including nabumetone. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) various skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely, bullous dermatoses (including epidermal necrolysis, erythema multiforme and exfoliative dermatitis). Psychiatric disorders
Uncommon: Confusion, nervousness, insomnia
Not known: Depression, hallucination
Nervous system disorders
Uncommon: Somnolence, dizziness, headache, paresthesia, anxiety
Not known: Drowsiness
Uncommon: Abnormal vision, eye disorder
Not known: Visual impairment
Ear and labyrinth disorders
Tinnitus, ear disorder Vertigo
Hypertension, cardiac failure
Cardiac disorders Not known:
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
Diarrhoea, constipation, dyspepsia, gastritis, nausea, abdominal pain, flatulence
Uncommon: Duodenal ulcer, GI bleeding, gastric ulcer, GI disorder, melena, 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 older people, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, dry mouth, faecal occult blood, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Very rare: Hepatic failure, jaundice
Not known: Hepatic function abnormal, hepatitis
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 Not known: Purpura
Musculoskeletal and connective tissue disorders Uncommon: Myopathy
Renal and urinary disorders Uncommon: Urinary tract disorder
Very rare: Renal failure, nephrotic syndrome
Not known: Interstitial nephritis
Reproductive system and breast disorders
Very rare: Menorrhagia
General disorders and administration site conditions Common: Oedema
Uncommon: Asthenia, fatigue
Not known: Malaise
Uncommon: Elevated liver function tests
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).
Reporting of suspected adverse reactions
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 Website: www.mhra.gov.uk/yellowcard
Signs and symptoms
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, hypotension, tinnitus, fainting, and 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.
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 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 the patient’s clinical condition.
Pharmacotherapeutic group: Other antiinflammatory and antirheumatic agents, non-steroids, ATC code: M01AX01.
Nabumetone is a non-acidic non-steroidal anti-inflammatory agent which is a relatively weak inhibitor of prostaglandin synthesis. A notable feature of the animal pharmacology is the lack of effect on the gastric mucosa. Nabumetone has a weak effect on platelet aggregation caused by collagen and no effect on bleeding time. In humans, lower frequency of peptic ulcers, bleeding or perforation has been reported in comparison with other NSAIDS. Following absorption from the gastrointestinal tract nabumetone is rapidly metabolised in the liver to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) a potent inhibitor of prostaglandin synthesis.
Nabumetone is absorbed almost entirely (>80%) from the gastrointestinal tract, but the first-pass metabolism is extensive, and no unchanged nabumetone is found in the plasma. The absorption rate is increased by concurrent ingestion of food or milk. The total quantity of the active metabolite in plasma is unchanged. In-vivo studies suggest that 6-MNA does not undergo any enterohepatic circulation. The bioavailability of 6-MNA in administration of nabumetone is approximately 35% (23-52%). The maximum plasma level of 6-MNA is reached at around 3 (1-12) hours after dosing.
6-MNA binds strongly to plasma proteins (>99%). The free fraction is dependent on the total concentration of 6-MNA and is proportional to dose in the range 1-2 g. The free fraction is 0.2-0.3% for 1 g daily dosing. Because of its strong binding to proteins, 6-MNA cannot be dialysed. Following intravenous administration, the distribution volume has been measured as 7.5 (6.8-8.4) l and clearance as 4.4 (1.0-6.9) ml/min.
Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character. 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 plasma elimination half-life is about one day in man.
The steady-state plasma concentration in older people 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.
In 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 concentrations of the active metabolite was equivalent to the values observed in healthy individuals.
There are no preclinical safety data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.
Cellulose microcrystalline Sodium laurilsulfate Saccharin sodium Hypromellose
Sodium starch glycolate (Type A)
The film-coating contains:
Hypromellose Titanium dioxide (E171)
Ponceau 4R (E124)
Sunset yellow aluminium lake (E110)
Do not store above 25°C. Blisters: Store in the original package in order to protect from light. Bottles: Keep the container tightly closed in order to protect from light.
Cartons containing PVdC coated PVC blister strips with aluminium foil lidding and polypropylene container with tamper-evident polyethylene closure with optional polyethylene ullage filler.
Available in packs of 10, 14, 20, 28, 30, 50, 56, 60, 100, 112, 168 and 250. Not all pack sizes may be marketed.
Generics [UK] Limited t/a Mylan