NABUMETONE 500 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Nabumetone 500mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Nabumetone 500 mg.

For excipients see 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Brown, capsule-shaped biconvex tablet marked ‚NEO‘ on one side ‚NBU500‘ on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Nabumetone is a non-acidic non-steroidal anti-inflammatory agent which is a relatively weak inhibitor of prostaglandin synthesis. However, following absorption from the gastrointestinal tract it is rapidly metabolised in the liver to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), a potent inhibitor of prostaglandin synthesis

For use in osteoarthritis and rheumatoid arthritis requiring anti-inflammatory and analgesic treatment.

4.2 Posology and method of administration

Method of Administration:

For oral administration.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Nabumetone 500 mg film-coated tablets should be taken preferably with or after food.

Posology:

Adults:

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.

Elderly:

In common with many drugs, blood levels may be higher in elderly patients. The recommended daily dose of 1 g should not be exceeded in this age group and in some cases 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.

Paediatric population:

There are no clinical data to recommend use of Nabumetone 500mg Tablets in children.

4.3 Contraindi­cations

Hypersensitivity to nabumetone or to any of the other excipients listed in section

6.1

Active, or history of recurrent peptic ulcer/ GI haemorrhage, perforation or peptic disease (two or more distinct episodes). NSAID's 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 antiinflammatory drugs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.

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 severe heart failure and in patients with current cerebrovascular or other haemorrhage

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal 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).

Elderly

The 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.

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 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 indicative for ulceration (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 postregistration 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 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.

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. 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.

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 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 mellitusand smoking).

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/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). 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.

Dermatological:

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.

Concomitant administration of nabumetone with other protein-bound drugs, e.g. sulphonamides, sulphonilureas or hydantoin should be undertaken with caution and overdose signals carefully monitored.

No specific interaction studies with Nabumetone and the above have been performed. Caution is therefore recommended for concomitant therapy with the drugs listed above.

4.6 Fertility, pregnancy and lactation

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 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 oligohydroamniosis; 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-feeding

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 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.

Fertility

See section 4.4 – Special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines

Undesirable effects such as dizziness, confusion, drowsiness, fatigue or visual disturbances are possible after taking NSAIDs.If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Summary of safety profile

Severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with nabumetone treatment (see section 4.4).

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 not know (cannot be estimated from the 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.

Very Rare: Thrombocytopenia,

Not known: Neutropenia, agranulocytosis, aplastic anaemia, leucopenia and haemolytic anaemia

Immune system disorders

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, drug reaction with eosinophilia and systemic symptoms, 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

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).

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed on this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

a) Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting and occasionally convulsions.

In cases of significant poisoning acute renal failure and liver damage are possible.

b) Therapeutic measure

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 patient’s clinical condition.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other anti-inflammatory and anti-rheumatic agents, non

steroids.

ATC code: M01AX01.

Nabumetone contains an active substance 4-(6’-methoxy-2’naphthyl)-2 butanone.

Nabumetone is a non acidic non steroidal anti-inflammatory agent with weak prostaglandin synthesis properties. 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 live to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) a potent inhibitor of prostaglandin synthesis.

5.2 Pharmacokinetic properties

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. Intravenous studies in rats with nabumetone indicate it to be rapidly distributed throughout the body, in keeping with its highly lipophilic character. The active metabolite 6-MNA 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 halflife is about 1 day in man.

The absorption rate is increased by concurrent ingestion of food or milk. However, 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.

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 and approximately 0.6–0.8% with 2 g daily dosing. Because of its strong binding to proteins, 6-MNA cannot be dialysed.

6-MNA is more than 99% bound to plasma protein and diffuses into synovial fluid.

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.

Elderly

The 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 Impairment

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 concentration of the active metabolite

was equivalent to the values observed in healthy individuals.

5.3 Preclinical safety data

No data of relevance which is additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch

Sodium Starch Glycollate (Type A)

Povidone

Sodium Lauryl Sulphate

Colloidal Silicon Dioxide

Magnesium Stearate

Film Coating:

Hypromellose

Titanium dioxide

Talc

Red iron oxide

Glycerol triacetate

6.2 Incompati­bilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Blisters of PVC/PVdC/aluminium.

Pack sizes of 8, 56 and 100 tablets.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Kent Pharma UK Limited,

The Bower,

4 Roundwood Avenue,

Stockley Park,

Heathrow,

United Kingdom, UB11 1AF.

8 MARKETING AUTHORISATION NUMBER(S)

PL 51463/0008

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

13/01/2012