Nabumetone

Increased risk of gastrointestinal ulceration or bleeding.

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.

In patients with severe renal impairment (creatinine clearance less than 30 ml/min):

Urine is the major excretion route for the metabolites of nabumetone. In patients with impaired renal function, 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. It is consistent with good clinical practice that patients with known renal impairment should be monitored regularly during therapy. 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.

Alcohol, bisphosphonates, oxpentifylline (pentoxyfilline) and sulfinpyrazone may potentiate GI side-effects and the risk of bleeding or ulceration.

Increased risk of gastrointestinal bleeding.

Reduced diuretic effects. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Such drugs may also induce hyperkalaemia when administered with potassium-sparing diuretics. Interaction studies between nabumetone and these other drugs have not been performed; caution in co-administration is therefore recommended.

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 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.

Hyperkalaemia might develop, particularly with concomitant potassium sparing diuretics administration.

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.

Increased risk of nephrotoxicity.

Co-administration reduces the metabolism and elimination of nabumetone.

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, 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.

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. 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.

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 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 mellitus, smoking). Since peripheral oedema has been observed with nabumetone therapy, the patient should be monitored for exacerbation of the existing condition and appropriate therapy instigated.

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

There is no clinical trial experience with the use of nabumetone during human pregnancy.

No teratogenic effects have been demonstrated in experiments with animals. High doses which were maternally toxic were also embryotoxic (rabbit 300mg/kg dose). High doses in rats (320 mg/kg dose) delayed parturition (thought to be due to inhibition of prostaglandin synthesis).

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetus (risk of closure of the ductus ateriosus, pulmonary and cardiac changes), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

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

The active metabolite of nabumetone has been found in the milk of lactating animals. The safety of nabumetone during breastfeeding in humans is not known, use is therefore not recommended.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breast-feeding.

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.

Dizziness, confusion, drowsiness, fatigue, visual disturbances or headaches are possible undesirable effects 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 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 disorders

Very Rare: Thrombocytopenia

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

Immune system disorders

Very rare: Anaphylaxis, anaphylactoid reaction

Psychiatric disorders

Uncommon: Confusion, nervousness, insomnia

Not known: Depression, hallucinations

Nervous system disorders

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), vertigo, drowsiness

Eye disorders

Uncommon: Abnormal vision, eye disorders

Not known: Optic neuritis

Ear and labyrinth disorders

Common: Tinnitus, ear disorder

Vascular disorders

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

Gastrointestinal disorders

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. Nausea vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been reported.

Hepatobiliary disorders

Very rare: Hepatic failure, jaundice

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

Investigations

Uncommon: Elevated liver function tests

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or © assorted skin disorders, including rashes of various type, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necroylsis and erythema multiforme).

Other adverse reactions reported

Neurological and special senses: Optic neuritis, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as a stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Renal: Nephrotoxicity in various forms, including interstitial nephritis,

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).

In clinical trials, increases in doses above 1 g did not lead to an increase in the incidence of side effects. However, the lowest effective dose should always be used.