NAPROXEN TABLETS BP 250mg

Each tablet contains 250mg Naproxen PhEur.

Yellow uncoated tablets.

Yellow, circular, flat bevelled-edge uncoated tablets impressed “C” and the identifying letters “NC” on either side of a central division line on one face.

Naproxen is indicated for the treatment of:

1) Rheumatoid arthritis.

2) Osteoarthritis (degenerative arthritis).

3) Ankylosing spondylitis.

4) Acute gout.

5) Acute musculoskeletal disorders such as cervical spondylitis, lumbosacral pain, direct trauma, strains and sprains, fibrositis and tenosynovitis.

Adults:

Rheumatoid arthritis, osteoarthritis and ankylosing spondylitis: 500mg-1g daily in two doses at twelve hour intervals, or alternatively, as a single administration of two tablets, morning or evening.

A loading dose of 750mg-1g daily for the acute phase is recommended in the following cases:

a) Patients reporting severe night time pain and/or morning stiffness.

b) Patients commencing naproxen therapy following a switch from a high dose of another antirheumatic compound.

c) Osteoarthritis where pain is the predominant symptom.

For patients requiring 750mg or 1g daily, the size of the morning and evening doses may be adjusted on the basis of the predominant symptoms eg night time pain or morning stiffness.

Acute gout: Initially 750mg followed by 250mg every 8 hours until the attack has passed.

Acute musculoskeletal disorders: Initially 500mg followed by 250mg every 6-8 hours as necessary to a maximum of 1250mg daily after the first day.

Children under 16 years: Not recommended.

Elderly: 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 patient should be monitored regularly for GI bleeding during NSAID therapy.

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

Route of administration

For oral administration preferably with or after food.

Patients with active peptic ulceration or a history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); known hypersensitivity to naproxen, naproxen sodium or any other ingredient in the formulation. NSAIDs 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 anti-inflammatory drugs. Patients with severe hepatic, renal and cardiac failure (see section 4.4), severe heart failure, a history of upper gastrointestinal bleeding or perforation related to previous NSAID therapy. During the third trimester of pregnancy (see section 4.6).

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 cardiovascular risks below).

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 coxibs and 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). Although data suggest that the use of naproxen (1000mg daily) may be associated with a lower risk, some risk cannot be excluded.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with naproxen 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).

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).

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 ot 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)

- in the elderly

- when used with alcohol

- in smoking

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, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. 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).

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.

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 the elderly. Renal function should be monitored in these patients (see also section 4.3).

Naproxen should be used with great caution where there is impairment of renal function; the monitoring of serum creatinine and/or creatinine clearance should be conducted in these.

Naproxen is not recommended in patients having baseline creatinine clearance less than 20ml/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 naproxen therapy. Some elderly patients 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.

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 function may be at a greater risk when taking naproxen.

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 naproxen dosing is unknown but it is prudent to use the lowest effective dose.

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).

Impaired female fertility

The use of naproxen 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 fertility, withdrawal of naproxen should be considered.

When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be withdrawn.

Dermatological

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 for 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. Naproxen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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

Patients who have coagulation disorders or who are receiving drug therapy that affects haemostasis should be carefully observed when given naproxen (see section 4.5).

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

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-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

The use of Naproxen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

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 papilledema, 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.

Interference in tests:

Naproxen therapy should be temporarily withdrawn 48 hours before adrenal function tests are performed as it may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.

Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on naproxen therapy, but no definite trend was seen in any test indicating toxicity.

Contains Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Naproxen is highly protein-bound hence patients receiving hydantoins, anticoagulants or a highly protein-bound sulphonamide should be closely monitored for signs of overdosage of these drugs. No interactions have beern observed in clinical studies with naproxen or sulphonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class.

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 4.4).

Naproxen reduces the effects of diuretics, also diuretics can increase the risk of nephrotoxicity of NSAIDs.

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels of cardiac glycosides.

There is an increased risk of nephrotoxicity with ciclosporin or tacrolimus.

If mifepristone is taken NSAIDs should not be used for 8-12 days after mifepristone administration as the NSAIDs can reduce the effect of the mifepristone.

There is an increased risk of gastrointestinal ulceration or bleeding with corticosteroids.

The effects or anti-coagulants, such as warfarin, may be enhanced by NSAIDs (see section 4.4.).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRls): Increased risk of gastrointestinal bleeding (see section 4.4).

Animal data indicates that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Therefore, Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

NSAIDs, including naproxen, have been reported to increase steady state plasma lithium levels, decreased elimination of lithium. It is recommended that these levels are monitored whenever initiating, adjusting or discontinuing naproxen.

Anti-hypertensives: Reduced anti-hypertensive effect. Concomitant administration of naproxen with beta blockers may reduce their antihypertensive effect and may increase the risk of renal impairment associated with the use of ACE inhibitors or angiotensin II receptor antagonists.

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

Caution is advised when methotrexate is administered concurrently, due to the possible enhancement of its toxicity as naproxen, like other NSAIDs, has been reported to reduce tubular secretion of methotrexate in an animal model. Decreased elimination of methotrexate.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haem arthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen

Bisphosphonates: concomitant use of bisphosphonates and NSAIDs may increase the risk of gastric mucosal damage.

Colestyramine: colestyramine delays the absorption of naproxen. Naproxen should be taken at least one hour before or four to six hours after colestyramine.

Pregnancy: 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 foetal cardiovascular system (risk of closure of the ductus arteriosus), 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 (see section 4.3). NSAIDs should not be used during the first two trimestersof pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

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

See section 4.4 for use regarding female fertility.

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

*especially in patients with existing auto-immune disorders, such as system lupus erythematosus, mixed connective tissue disease, with symptoms such as stiff neck headache, nausea, vomiting, fever and disorientation.

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.

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 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.

Naproxen is a non-steroidal anti-inflammatory agent.

Naproxen reduces the synthesis of prostaglandins primarily by inhibiting the enzyme cyclo-oxygenase. Naproxen has been shown to have anti-inflammatory activity in a number of experimental models. Naproxen inhibits prostaglandin E₂ synthesis in vitro by human rheumatoid synovial microsomes. It also inhibits prostaglandin E₂ production by phytohaemagglutin-stimulated peripheral blood mononuclear cells. At 10^-4 M (23mg.1^-1) naproxen inhibits neutral protease activity derived from human polymorphonuclear leucocytes. Naproxen also inhibits in vitro the activity of cathepsin-β and other hydrolytic enzymes derived from lysosomes. Naproxen is a potent in inhibitor of leucocyte migration and produces effects comparable to those of colchicine.

Naproxen is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are attained 2-4 hours after ingestion. Plasma concentrations of naproxen increase proportionally with dose up to about 500mg daily; at higher doses there is an increase in clearance caused by saturation of plasma proteins. At therapeutic concentrations naproxen is more than 99% bound to plasma proteins and has a plasma half-life of about 13 hours. Approximately 95% of a dose is excreted in urine as naproxen and 6-O-desmethylnaproxen and their conjugates. Less than 3% of a dose has been recovered in the faeces. Naproxen crosses the placenta and is excreted in breast milk.

Not applicable.

Also contains: lactose, magnesium stearate, maize starch, polyvidone, E172, E463.

None known.

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

Store below 25°C in a dry place. Protect from light.

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-6g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 20s, 28s, 30s, 50s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

Not applicable.

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

PL 0142/0277

16.05.90

07.06.2011