NAPROSYN EC

Posology

For oral administration

Naprosyn EC tablets should be swallowed whole and not broken or crushed.

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

Adults:

Rheumatoid arthritis, osteoarthritis and ankylosing spondylitis:

The usual dose is 500mg to 1g daily taken in two doses at 12-hour intervals. Where 1g per day is needed one 500mg tablet twice daily or two 500mg tablets in a single administration (morning or evening) is recommended.

Acute gout:

The use of Naprosyn with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors 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). Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

Gastrointestinal ulceration, bleeding and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime 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 section 4.5).

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). Patients with a history of GI toxicity, particularly in older people, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. When GI bleeding or ulceration occurs in patients receiving Naprosyn, the treatment should be withdrawn. Episodes of gastro-intestinal bleeding have been reported in patients with naproxen therapy. Naprosyn EC should be given under close supervision to patients with a history of gastro-intestinal disease.

Studies to date have not identified any subset of patients not at risk of developing peptic ulcer and bleeding. However, older people and debilitated patients tolerate gastro-intestinal ulceration or bleeding less well than others. Most of the serious gastro-intestinal events associated with non-steroidal anti-inflammatory drugs occurred in this patient population.

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, selective serotonin-uptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

Precautions related to older people

Older people have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal. In older people the clearance is reduced. Use of the lower end of the dosage range is recommended (see section 4.2).

Prolonged use of NSAIDs in older people is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.

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).

Skin reactions

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Naprosyn should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Anaphylactic (anaphylactoid) reactions:

Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory drugs or naproxen-containing products. They may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.

Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Renal Effects

There have been reports of impaired renal function, renal failure, acute interstitial nephritis, haematuria, proteinuria, renal papillary necrosis and occasionally nephrotic syndrome associated with naproxen.

Renal failure linked to reduced prostaglandin production

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, angiotensin converting enzyme inhibitors, angiotensin-II receptor antagonists and older people. Renal function should be monitored in these patients.

Use in patients with impaired renal function:

As naproxen is eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised and patients should be adequately hydrated. Naprosyn EC is not recommended in patients having a baseline creatinine clearance of less than 30 ml/minute.

Certain patients, specifically those whose renal blood flow is compromised, because of extracellular volume depletion, cirrhosis of the liver,

sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during Naprosyn EC therapy. Some older people in whom impaired renal function may be expected, as well as patients using diuretics, may also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.

Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding.

Use in patients with impaired liver function:

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for Naprosyn EC dosing is unknown but it is prudent to use the lowest effective dose.

Hepatic effects

As with other non-steroidal anti-inflammatory drugs, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal) have been reported with this drug as with other non-steroidal anti-inflammatory drugs. Cross reactivity has been reported.

Haematological:

Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered.

Patients at high risk of bleeding or those on full anti-coagulation therapy (e.g. dicoumarol derivatives) may be at increased risk of bleeding if given naproxen- containing products concurrently.

Antipyretic effects:

The antipyretic and anti-inflammatory activities of Naprosyn EC may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.

Steroids:

If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Ocular effects:

Studies have not shown changes in the eye attributable to naproxen administration.

In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including naproxen, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with naproxen-containing products should have an ophthalmological examination.

Sodium/fluid retention in cardiovascular conditions and peripheral oedema

Mild peripheral oedema has been observed in a few patients receiving naproxen.

Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Naprosyn EC.

Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Cardiovascular and cerebrovascular effects:

Concomitant administration of an antacid or colestyramine can delay the absorption of naproxen but does not affect its extent. Concomitant administration of food can delay the absorption of naproxen, but does not affect its extent.

Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anticoagulants, other NSAIDs, aspirin or a highly protein- bound sulfonamide should be observed for signs of overdosage of these drugs. Patients simultaneously receiving Naprosyn EC and a hydantoin, sulfonamide or sulfonylurea should be observed for adjustment of dose if required.

It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

No interactions have been observed in clinical studies with naproxen and anticoagulants or sulfonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class. NSAIDs may enhance the effects of anti-coagulants such as warfarin.

The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported.

Naproxen and other non-steroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers and may increase the risk of renal impairment associated with the use of ACE-inhibitors.

Diuretics, ACE inhibitors and Angiotensin II Antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or older people with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking naproxen concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in older people. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

Probenecid given concurrently increases naproxen plasma levels and extends its half- life considerably.

Caution is advised where methotrexate is administered concurrently because of possible enhancement of its toxicity, since naproxen, in common with other non- steroidal anti-inflammatory drugs, has been reported to reduce the tubular secretion of methotrexate in an animal model.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.

As with all NSAIDs caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.

NSAIDs should not be used for 8 - 12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.

As with all NSAIDs, caution should be taken when co-administering with cortico- steroids because of the increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

The concomitant administration of two or more NSAIDs should be avoided. Patients taking quinolones may have an increased risk of developing convulsions.

It is suggested that Naprosyn EC therapy be temporarily discontinued 48 hours before adrenal function tests are performed, because naproxen may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.

There is an increased risk of gastrointestinal bleeding (see section 4.4) when anti- platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.

There is an 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.

The following adverse events have been reported with NSAIDs and naproxen:

Gastro-intestinal: The most commonly observed adverse events are gastrointestinal in nature. Inflammation, bleeding (sometimes fatal, particularly in older people), ulceration, perforation and obstruction of the upper and lower gastrointestinal tract (see section 4.4). Heartburn, nausea, oesophagitis, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, stomatitis, exacerbation of ulcerative colitis and Crohn’s disease (see section 4.4), pancreatitis and gastritis have been reported following administration.

Blood and lymphatic system disorders: thrombocytopenia, granulocytopenia including agranulocytosis, aplastic anaemia, eosinophilia, leucopoenia and haemolytic anaemia

Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs in patients with, or without, a history of previous hypersensitivity reactions to NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angio-oedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).