ARTHROSIN EC 500, NAPROXEN 500 MG GASTRO-RESISTANT TABLETS, NYCOPREN TABLETS 500 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Nycopren 500 mg

Naproxen 500 mg Gastro-resistant Tablets

Arthrosin EC 500

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Naproxen BP 500 mg

Excipients(s) with known effect

Each tablet contains 36.000 mg of lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Gastro-resistant tablets for oral administration.

White oblong tablets with a break line engraved on one side with approximately 16 mm diameter.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

Naproxen is used in the treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis), ankylosing spondylitis, acute gout and acute inflammatory musculoskeletal disorders.

Children

Naproxen is effective in the treatment of juvenile rheumatoid arthritis in children over 5 years of age.

4.2 Posology and method of administration

Posology

Adult

dosage:

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

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

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

Acute gout:

750 mg at once then 250 mg every 6 – 8 hours until the attack has passed.

Acute inflammatory musculoskeletal disorders

500 mg initially, followed by 250 mg 6 – 8 hour in intervals as needed. Maximum daily dose is 1250 mg.

Paediatric population (over 5 years)

For juvenile rheumatoid arthritis:

A dose of 10 mg per kg body weight daily in two divided doses taken in children over 5 years of age with juvenile rheumatoid arthritis.

Naproxen is not recommended for use in any other indication in children under 16 years of age.

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. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for naproxen dosing is unknown. As with other drugs used in the elderly it is prudent to use the lowest effective dose and for the shortest duration possible as older people are more prone to adverse events. For the effect of reduced elimination in the elderly refer to Section 4.4

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

Renal/hepatic impairment:

A lower dose should be considered in patients with renal or hepatic impairment (See other special warnings and precautions).

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

Naproxen is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of naproxen metabolites has been seen in

patients with severe renal failure or those on dialysis (see section 4.3).

Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

Method of administration

For oral administration, to be taken preferably with or after food.

4.3 Contraindications

NSAIDs are contraindicated in patients who have:

Hypersensitivity to naproxen, naproxen sodium or any of the excipients listed in section 6.1.

Patients with active gastrointestinal bleeding.

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

NSAID’s contra­indicated in patients who have p reviously shown hypersensitivity reactions, Naproxen should not be given to patients in whom aspirin or other non-steroidal anti-inflammatory/a­nalgesic drugs induce the syndrome of asthma, rhinitis, nasal polyps or urticaria or other non-steroidal anti-inflammatory drugs. These reactions have the potential of being fatal. Severe anaphylactic-like reactions to naproxen have been reported in such patients.

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

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

Naproxen is contraindicated during the last trimester of pregnancy (See section 4.6).

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 GI and cardiovascular risks below). Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

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

Older people and/or debilitated patients are particularly susceptible to the adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal (See section 4.2 – Posology and administration). Prolonged use of NSAID’s in these patients is not recommended. When prolonged therapy is required, patients should be reviewed regularly.

Respiratory disorders:

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

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.

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

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 Naproxen.

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 gastro-toxicity 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.

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).

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 (see also Section 4.3).

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 significantly impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised and patients should be adequately hydrated. Naproxen is contraindicated in patients having baseline creatinine clearance less than 30ml/minute.

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

Certain patients, specifically those where renal blood flow is compromised, such as in 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 older people, in whom impaired renal function may be expected, could also fall within this category. A reduction in the daily dosage should be considered to avoid the possibility of excessive accumulation of Naproxen metabolites in these patients.

Use in patients with impaired liver function

Chronic alcoholic liver disease and probably other forms of cirrhosis reduce the total plasma concentration of Naproxen but the plasma concentration of unbound Naproxen is increased, so caution is advised when high doses are required. The implication of this finding for naproxen dosing is unknown but it is prudent to use the lowest effective dose.

Haematological

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.

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 (eg asthma), rhinitis and nasal polyps.

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

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 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.

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).

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).

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.

Combination with other NSAIDs

The combination of naproxen-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events. (See section 4.5 Interactions).

Contains lactose; Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction Antacid or colestyramine: Concomitant administration of 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.

It is considered unsafe to take NSAIDs in combination with anti-coagulants such as warfarin or heparin unless under direct medical supervision, as NSAIDs may enhance the effects of anti-coagulants (see Section 4.4).

Other analgesic including cyclooxygenase-2 selective inhibitors: Due to increased risk of adverse effects, avoid concomitant administration of two or more NSAIDs, including aspirin as this may increase the risk of adverse effects (See section 4.4).

Acetylsalicylic acid

Clinical pharmacodynamic data suggest that concomitant naproxen usage for more than one day consecutively may inhibit the effect of low-dose acetylsalicylic acid on platelet activity and this inhibition may persist for up to several days after stopping naproxen therapy. The clinical relevance of this interaction is not known.

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

Diuretics:

Caution is advised when Naproxen is co-administered with diuretics as there can be a decreased diuretic effect. 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.

Lithium: The renal clearance of lithium may be inhibited leading to increases in plasma lithium concentrations has also been reported, as may the natriuretic action of furosemide.

Anti-hypertensives: Naproxen and other non-steroidal anti-inflammatory drugs can reduce anti-hypertensive effect, in particular for propranolol and other betablockers. Concomitant use of NSAIDs with ACE inhibitors or angiotensin-II receptor antagonists may increase the risk of renal impairment, especially in patients with pre-existing poor renal function (See Section 4.4).

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

Methotrexate: Caution is advised where methotrexate is given concurrently because of possible enhancement of its toxicity, since naproxen, among other nonsteroidal anti-inflammatory drugs, has been reported to reduce the tubular secretion of methotrexate in an animal model.

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

Ciclosporin: As with all NSAIDs caution is advised when ciclosporin is coadministered because of the increased risk of nephrotoxicity.

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

Corticosteroids: As with all NSAIDs, caution should be taken when coadministering with cortico-steroids because of the increased risk of gastrointestinal ulceration or bleeding.

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.

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

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

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

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.

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

4.6 Fertility, pregnancy and lactation

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. As with other drugs of this type, naproxen produces delay in parturition in animals and also affects the human foetal cardiovascular system (risk of closure of the ductus arteriosus). Use of Naproxen in the last trimester of pregnancy is contraindicated (See section 4.3). 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.

Labour and delivery:

Naproxen containing products are not recommended in labour and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect foetal circulation and inhibit contractions, with an increased bleeding tendency in both mother and child.

Breast feeding:

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.

Fertility:

The use of naproxen, as with any drug known to inhibit cyclooxygenase/pros­taglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of naproxen should be considered.

4.7 Effects on ability to drive and use machines

If CNS side effects such as Some patients may experience dizziness, drowsiness, vertigo, insomnia, fatigue, visual disturbances and depression with the use of Naproxen. If should occur (most likely at high doses), patients experience these or similar undesirable effects, they should not drive or operate machinery.

4.8 Undesirable effects

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

Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Heartburn, nausea, vomiting, constipation, diarrhoea, flatulence, dyspepsia, abdominal discomfort and epigastric distress. More serious reactions which may occur are gastro-intestinal bleeding, which is sometimes fatal, particularly in older people (see section 4.4), inflammation, ulceration, perforation, and obstruction of the upper and lower gastrointestinal tract, melaena, haematemesis, stomatitis, exacerbation of ulcerative colitis and Crohn’s disease (see section 4.4), oesophagitis, gastritis and pancreatitis.

Blood and lymphatic disorders: Thrombocytopenia, neutropenia, granulocytopenia including agranulocytosis, eosinophilia, leucopenia, aplastic anaemia and haemolytic anaemia.

Immune system disorders: Hypersensitivty 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 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 © 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).

Metabolic and nutrition disorders: Hyperkalaemia

Psychiatric disorders: Insomnia, dream abnormalities, depression, confusion and hallucinations.

Nervous system disorders: Convulsions, dizziness, headache, lightheadedness, drowsiness, paraesthesia, retrobulbar optic neuritis, inability to concentrate and cognitive dysfunction have been reported. 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).

Eye disorders: Visual disturbances, corneal opacity, papillitis and papilloedema

Ear and Labyrinth disorders: Tinnitus, hearing disturbances including impairment and vertigo

Cardiovascular: Oedema, palpitations, cardiac failure and congestive heart failure has been reported in association with NSAID treatment.

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) (see section 4.4).

Vascular disorder: Hypertension, vasculitis.

Respiratory, thoracic and mediastinal disorder: Dyspnoea, asthma, eosinophilic pneumonitis and pulmonary oedema.

Hepatobiliary disorders: Jaundice, fatal hepatitis and abnormal liver function tests.

Skin and subcutaneous tissue disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, Stevens-Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis and very rarely toxic epidermal necrolysis, photosensitivity reactions (including cases in which the skin resembles porphyria cutanea tarda, ‘pseudoporphyria’) or epidermolysis bullosa-like reactions which may occur rarely.

If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Musculoskeletal and connective tissue disorders: Myalgia and muscle weakness

Renal and urinary disorders: Including but not limited glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, raised serum creatinine renal papillary necrosis and renal failure.

Reproductive system and breast disorders: Female infertility

General disorder and administration site complications: Thirst, pyrexia, fatigue and malaise.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Symptoms include headache, heartburn, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting. In cases of significant poisoning acute renal failure and liver damage are possible.

Respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.

In one case of naproxen overdose, transient prolongation of the prothrombin time due to hypothrombinaemia may have been due to selective inhibition of the synthesis of vitamin-K dependent clotting factors.

A few patients have experienced seizures, but it is not known whether these were naproxen-related or not. It is not known what dose of naproxen will be life threatening. Management

Patients should be treated symptomatically as required. 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 lifethreatening 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.

Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.

5 PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, nonsteroids. Propionic acid derivatives.

ATC code: M01AE02

Naproxen is a non-steroidal anti-inflammatory agent (NSAID) with analgesic and antipyretic properties as has been demonstrated in classical animal test systems. Naproxen exhibits its anti-inflammatory effect even in adrenalectomised animals, indicating that its action is not mediated through the pituitary-adrenal axis. Naproxen inhibits prostaglandin synthetase, as do other non-steroidal antiinflammatory agents (NSAIDs). As with other (NSAIDs), however, the exact mechanism of its anti-inflammatory action is not known.

5.2 Pharmacokinetic properties

Absorption

Naproxen is readily absorbed from the gastro intestinal tract, and peak plasma levels are reached in 2 to 4 hours.

Distribution

Naproxen is present in the blood mainly as unchanged drug, extensively bound to plasma proteins. The plasma half-life in between 12 and 15 hours, enabling a steady state to be achieved within 3 days of initiation of therapy on a twice daily dose regimen. The degree of absorption is not significantly affected by either foods or most antacids.

Elimination

Excretion is almost entirely via the urine, mainly as conjugated naproxen, with some unchanged drug. Metabolism in children is similar to that in adults. Chronic alcoholic liver disease reduces the total plasma concentration of naproxen but the concentration of unbound naproxen increases. In older people, the unbound plasma concentration of naproxen is increased although total plasma concentration is unchanged.

5.3 Preclinical safety data

Carcinogenicity

Naproxen was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24mg/kg/day. Naproxen was not carcinogenic in rats.

Mutagenicity

Mutagenicity was not seen in Salmonella typhimurium (5 cell lines), Sachharomyces cerevisisae (1 cell line), and mouse lymphoma tests.

Fertility

Naproxen did not affect the fertility of rats when administered orally at doses of 30mg/kg/day to males and 20mg/kg/day to females.

Teratogenicity

Naproxen was not teratogenic when administered orally at dose of 20mg/kg/day during organogenesis to rats and rabbits.

Perinatal/Postnatal Reproduction

Oral administration of naproxen to pregnant rats at doses of 2, 10 and 20mg/kg/day during the third trimester of pregnancy resulted in difficult labour. These are known effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indometacin.

6.1 List of excipients

Lactose, potato starch, povidone K-90, glycerolum, sodium starch glycolate, magnesium stearate, simethicone emulsion.

The film contains:

Eudragit L12.5 and L30 D, triacetin, talc, polyethylene glycol 600, simethicone emulsion.

6.2 Incompatibilities

Not applicable

6.3

4 years, polypropylene containers 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

Pack size: 20, 28 and 56

Polypropylene container and polyethylene cap

Pack size: 8, 56, 60, 84, 100, 250

6.6 Special precautions for disposal

Gastro-resistant tablets should be swallowed whole preferably with sufficient to drink.

7 MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

11 Boumpoulinas Street,

3rdFloor, 1060 Nicosia

Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 33414/0145