Document: document 1 change

• document 0
• document 1

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nycopren 250 mg

Naproxen 250 mg Gastro-resistant Tablets Arthrosin EC 250

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Active constituent:

Naproxen BP 250 mg

Also contains lactose. See section 6.1 for excipients.

3    PHARMACEUTICAL FORM

Gastro-resistant tablets for oral administration.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthrosis (degenerative arthritis), ankylosing spondylitis, acute gout and acute inflammatory musculoskeletal disorders.

4.2 Posology and method of administration

For oral administration.

To be taken preferably with or after food.

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

Adult dosage:

a) Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis: 500 mg to 1 g per day taken in 2 doses at 12 hour intervals.

b)    In severe night-time pain and/or morning stiffness, in patients being switched to Naproxen from a high dose of another NS AID, or in osteoarthrosis where pain is the predominant symptom:

Loading dose of 750 mg - 1 g per day during the acute phase.

c)    Acute gout:

750 mg at once then 250 mg every 8 hours until the attack has passed.

d)    Acute inflammatory musculoskeletal disorders:

500 mg initially, followed by 250 mg 8 hour in intervals as needed. Maximum daily dose is 1250 mg.

Use in children over 50 kg:

In juvenile rheumatoid arthritis, the dosage is as the adult dose in rheumatoid arthritis.

Use in the 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.

For Naproxen Gastro-resistant Tablets, adult doses may be used but with caution (when high doses are required).

Dosage in patients with renal impairment:

A reduction in dosage may be necessary if there is impaired renal function.

Use with caution if renal impairment is significant. Do not use if creatinine clearance is less than 20 ml/minute.

4.3 Contraindications

NSAIDs are contraindicated in patients who have:

•    Active or history of recurrent peptic ulceration / haemorrhage (two or more distinct episodes of proven ulceration or bleeding),

•    Hypersensitivity to naproxen or to any of the other constituents,

•    Previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other nonsteroidal anti-inflammatory drugs,

•    Severe hepatic, renal and cardiac failure (See section 4.4 - Special warnings and precautions for use),

•    A history of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

•    During the last trimester of pregnancy (See section 4.6 - Pregnancy and lactation)

4.4 Special warnings and precautions for use

In all patients:

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).

Gastro-resistant products cause less gastric irritation and are generally preferable.

The use of Naproxen with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors should be avoided (See section 4.5 Interactions).

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 - Posology and administration).

Respiratory disorders:

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

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 (1000 mg 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 events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Cardiovascular, Renal and Hepatic Impairment:

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients with compromised cardiac function may be at greater risk of sodium retention. Naproxen decreases platelet aggregation and prolongs bleeding time. Mild peripheral oedema may occur.

Use with great caution in patients with significantly impaired renal function. Use with caution in patients with impaired hepatic function, those taking diuretics and the elderly. Renal function should be monitored in these patients. (See section 4.3 - Contraindications).

Gastrointestinal bleeding, ulceration and perforation:

Although gastro-resistant NSAIDs cause less gastric irritation, 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).

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 - Undesirable effects).

Patients with a history of GI toxicity, particularly when elderly, 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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (See section 4.5 Interactions).

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

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 - Undesirable effects).

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 infertility, withdrawal of naproxen should be considered.

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 leisions or any other sign of hypersensitivity.

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

4.5 Interaction with other medicinal products and other forms of interaction

Other analgesic including cyclooxygenase-2 selective inhibitors: Due to increased risk of adverse effects, avoid concomitant administration of two or more NSAIDs, including aspirin (See section 4.3 Contraindications).

Anti-hypertensives: Reduced anti-hypertensive effect, in particular for propranolol and other beta-blockers.

Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides (e.g. digoxin): NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: The renal clearance of lithium may be inhibited, as may the natriuretic action of furosemide.

Methotrexate: Tubular secretion of methotrexate has been reported to be reduced in animal models, so increasing methotrexate toxicity, therefore caution is advised.

Ciclosporin: Use with ciclosporin increases the risk of nephrotoxicity. Concomitant use with ketorolac should be avoided due to increased risk of side effects and haemorrhage.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients who take NSAIDs with quinolones possibly increases the risk of convulsions.

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

Corticosteroids: Corticosteroids increase the risk of gastro-intestinal bleeding and ulceration. (See section 4.4 - Special warnings and precautions for use).

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin.

Patients receiving anticoagulants or highly protein bound sulphonamides should be observed for signs of overdosage due to naproxen protein binding (See section 4.4 - Special warnings and precautions for use).

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

Antiepileptics: Effect of phenytoin or hydantoin is enhanced by azapropazone and possibly other NSAIDs, like naproxen.

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.

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

Naproxen may interfere with some tests for 17-ketogenic steroids or assays for urinary 5-hydroxyindoleacetic acid.

4.6 Fertility, Pregnancy and lactation

Pregnancy:

Although, teratology studies in rats and rabbits, at high doses, have not produced evidence of foetal damage with naproxen, 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 -Contraindications). 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.

Lactation:

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

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

4.7 Effects on ability to drive and use machines

If CNS side effects such as headache, dizziness, drowsiness, fatigue, visual disturbances and insomnia should occur (most likely at high doses), patients should not drive or operate machinery.

4.8 Undesirable effects

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers (sometimes with haemorrhage and perforation) or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, anorexia, vomiting, epigastric distress, abdominal pain, constipation, dyspepsia, melaena, haematemesis, flatulence, ulcerative stomatitis, diarrhoea, exacerbation of colitis and Crohn’s disease (See section 4.4 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: Hypersensitivty reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylactic reactions to naproxen and naproxen sodium formulations (eosinophilic pneumonia may occur rarely) (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angio-oedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular: Oedema has 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 a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Other adverse events reported less commonly include:

Renal: Nephrotoxicity in various forms, including glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, renal papillary necrosis and renal failure.

Hepatic: Abnormal liver function, hepatitis and jaundice.

Neurological and special senses: Visual disturbances, optic neuritis, paraesthesia, headaches, hearing impairment, pancreatitis, alveolitis. Reports of induction or exacerbation of colitis and aseptic meningitis (especially in patients with existing auto-immune 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), depression, confusion, hallucinations, tinnitus, vertigo, malaise, fatigue dizziness, nervousness, insomnia, inability to concentrate, cognitive dysfunction and drowsiness.

Haematological: Thrombocytopenia, neutropenia, granulocytopenia, aplastic anaemia and haemolytic anaemia may occur rarely.

Dermatological: Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely. Photosensitivity.

4.9 Overdose

Symptoms

Significant overdosage may be characterized by:

Headache, tinnitus, drowsiness, indigestion, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, tachycardia, hypoprothrombinaemia and renal dysfunction.

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

Therapeutic measure

Treatment is supportive and symptomatic. Within one hour of ingestion of potentially toxic amount, activated charcoal may be given. Alternatively, in adults, the stomach should be emptied by lavage or inducing emesis 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 patients’s clinical condition. Further treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Naproxen is a non-steroidal anti-inflammatory agent (NSAID) with analgesic and antipyretic properties. It inhibits prostaglandin synthesis, as do other nonsteroidal anti-inflammatory agents. As with other agents, however, the exact mechanism of its anti-inflammatory action is not known.

5.2 Pharmacokinetic properties

Naproxen is a gastro-resistant tablet with an acid resistant film, and will pass through the stomach without disintegrating. In the intestine, the coating dissolves and naproxen is absorbed.

Complete absorption of Naproxen occurs, commencing 1-2 hours after ingestion. The peak plasma level occurs after 4-6 hours depending upon food intake. More than 99% of the drug is protein-bound, with only a small amount being distributed to the tissues. The half-life is between 10-17 hours, and averages 13 hours; this being virtually independent of dose. Naproxen is metabolized mainly by demethylation and conjugation, and is excreted in the urine (95%), mostly as inactive metabolites; with 10% being unchanged naproxen. 1-2% is excreted in the faeces.

5.3 Preclinical safety data

The toxicological profile of naproxen is well known and documented, and no additional toxicity studies have been performed with Naproxen.

6.1    List of excipients

Lactose, potato starch, povidone K-90, glycerolum, sodium starch glycolate, magnesium stearate, silicone antifoam 1510.

The film contains:

Eudragit L12.5, Eudragit L30 D, Triacetin, Talc, Polyethylene glycol 600, Silicone antifoam 1510.

6.2    Incompatibilities

Not applicable

6.3    Shelf life

4 years, Polypropylene container and blister pack.

6.4    Special precautions for storage

None.

Should be kept in a well closed container,

6.5    Nature and contents of container

Aluminium foil and PVC blister pack Polypropylene container and polyethylene cap