This information is intended for use by health professionals

1. Name of the medicinal product

Naproxen 250mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 250 mg naproxen

Excipient with known effect : Lactose monohydrate

Each tablet contains 72 mg of lactose monohydrate

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White to off white circular flat faced bevelled edge , uncoated tablet with inscription 'AP' on one side and breakline on the other side

4. Clinical particulars
4.1 Therapeutic indications

Adults:

Treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis), ankylosing spondylitis, acute gout, acute musculoskeletal disorders and dysmenorrhoea.

Children:

Juvenile rheumatoid arthritis

4.2 Posology and method of administration

Posology

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

Method of administration

For oral administration.

To be taken preferably with or after food

Rheumatic arthritis, osteoarthritis and ankylosing spondylitis (Adults):

500mg to 1g taken in 2 doses at 12-hour intervals or alternatively, as a single administration. In the following cases a loading dose of 750mg or 1g per day for the acute phase is recommended:

a) In patients reporting severe night-time pain/or morning stiffness.

b) In patients being switched to Naprosyn from a high dose of another anti-rheumatic compound.

c) In osteoarthrosis where pain is the predominant symptom.

Acute Gout (Adults): In acute gout an initial dose of 750 mg followed by 250mg every 8 hours until attack has passed; has been suggested.

Musculoskeletal Disorders and Dysmenorrhoea (Adults); 500mg may be given initially followed by 250mg every 6 to 8 hours as required. Maximum daily dose after first day is 1250mg daily.

Older people: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in older people. The implication of this finding for Naprosyn dosing is unknown. As with other drugs used in older people it is prudent to use the lowest effective dose and for the shortest duration possible as older people patients are more prone to adverse events. The patient should be monitored regularly for GI bleeding during NSAID therapy. For the effect of reduced elimination in older people refer to Section 4.4.

Pediatric population (over 5 years)

For juvenile rheumatoid arthritis: A dose of 10mg per kg body weight daily in two divided doses at 12-hour intervals has been used in children over 5 years of age. Naproxen tablets are not recommended for use in any other indication in children under 16 years of age.

Renal/hepatic impairment: A lower dose should be considered in patients with renal or hepatic impairment. Naprosyn 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.

4.3 Contraindications

• Hypersensitivity to any of the constituents.

• Since the potential exists for cross-sensitivity reactions, naproxen is contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, nasal polyps, angioedema or urticaria) in response to ibuprofen, aspirin, 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 heart failure, hepatic failure and renal failure (See section 4.4 - Special warnings and precautions for use).

• Third trimester of pregnancy (See section 4.6 - Pregnancy and lactation)

• A history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy. Active, or history of peptic ulcer/or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding).

• In principle, naproxen must not be administered to patients with gastrointestinal ulcerations, congestive gastritis or atrophic gastritis, gastrointestinal bleeding or other bleeding such as cerebrovascular bleeding.

• Hemorrhoids or predisposition to rectal bleeding.

4.4 Special warnings and precautions for use

In all patients:

Undesirable effects may be minimised by using the minimum effective dose for the shortest possible 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.

Older People:

Older people 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). Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required patients should be reviewed regularly

Severe gastrointestinal side effects may occur in patients who use prostaglandin synthetase inhibitors. The risk of developing gastrointestinal ulcers or bleeding increases with the duration of use and dose of naproxen. This risk is not limited to a specific patient population, but older people and debilitated individuals exhibit poorer tolerance to gastrointestinal ulceration or bleeding than others. The majority of fatal gastrointestinal effects attributed to prostaglandin synthetase inhibitors occurred in this population.

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

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.

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

Renal and Hepatic Impairment:

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, especially in the case of long-term treatment, those taking diuretics and older people Care must also be taken to ensure adequate diuresis. In the event of reduced renal perfusion, it is recommended to monitor renal function before and during treatment with naproxen (See also section 4.3-Contraindications).

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 in these patients. Naproxen is contraindicated in patients having a baseline creatinine clearance of less than 30ml/minute.

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

Certain patients, specifically those whose 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 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.

Use in patients with impaired liver function

Care should also be exercised in patients with hepatic insufficiency.

Caution is advised when high doses of naproxen are administered to older people patients, because there are indications that the quantity of non-protein-bound naproxen increases in such patients. Since naproxen has an anti-inflammatory, analgesic and antipyretic effect, certain symptoms of infection can therefore be masked.

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.

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.

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 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), when used with alcohol, in smoking and in older people. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when older people, 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, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5- Interactions). If a corticosteroid is replaced by naproxen and the substitution occurs partially or fully, the usual precautions which come into consideration when discontinuing corticosteroid treatment should be applied.

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)

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 section 4.5).

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 who use coumarin derivatives or heparin alongside naproxen have an increased risk of bleeding. The benefits in that case should be weighed up against the risks. In any case concomitant use of naproxen with a high dose of heparin (or derivatives thereof) is not recommended.

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 angio-oedema, bronchospastic reactivity (e.g. 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 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.

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.

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 Naproxen.

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

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 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions 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. If the skin becomes delicate or in the event of blistering or other symptoms of pseudoporphyria, treatment should be discontinued and the patient should be carefully monitored.

Combination with other NSAIDs including cyclooxygenase-2 selective inhibitors

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.

SLE and mixed connective tissue disease:

In patients with systemic lupus erythrematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8 - Undesirable effects).

Interference in tests:

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. 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 deficiencyor glucose-galactose malabsorption should not take this medicine.

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. Naproxen should be taken at least one hour before or four to six hours after colestyramine.

Food: Concomitant administration of food can delay the absorption of naproxen, but does not affect its extent.

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)

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.

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.

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

Lithium: Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported following administration of these agents.

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

Ciclosporin: Increased risk of nephrotoxocity.

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 co-administering with cortico-steroids because of the increased risk of gastrointestinal ulceration or bleeding.

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of GI bleeding (see section 4.4 – Special warning and precautions for use) when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.

Anti-coagulants : 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).

Effect of high plasma protein binding of Naproxen on other drugs:

Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anticoagulants, other NSAIDs, aspirin or a highly protein-bound sulphonamide should be observed for signs of overdosage of these drugs. Patients simultaneously receiving Naproxen and a hydantoin, sulphonamide 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.

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

Zidovudine: 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.

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

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

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

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.

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 (closure of ductus arteriosus). Use of Naprosyn in the last trimester of pregnancy is contraindicated (see Section 4.3). NSAIDs should not be used during the first two trimesters of pregnancy, 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

Naproxen has been found in the milk of lactating women. The use of Naprosyn should 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

Undesirable effects such as dizziness, vertigo, insomnia, drowsiness, fatigue and visual disturbances or depression are possible after taking Naproxen. If patient experiences 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 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 system disorders: Neutropenia, thrombocytopenia, granulocytopenia including agranulocytosis, eosinophilia, leucopenia, aplastic anaemia 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, angiodema 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

Cardiac disorders: Oedema, palpitations, cardiac failure and congestive heart failure have 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 disorders: Hypertension, vasculitis.

Hepatobiliary disorders:abnormal liver function, hepatitis (including some fatalities) and jaundice.

Nervous system disorders: convulsions, dizziness, headache, lightheadedness, drowsiness, inability to concentrate and cognitive dysfunction, retrobulbar optic neuritis, paraesthesia, exacerbation of parkinson's disease, 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 stiff neck, headache, nausea, vomiting, fever and disorientation (see section 4.4), nervousness, euphoria, low temperature and drowsiness.

Haematological: Thrombocytopenia, eosinophilia, leucopenia, neutropenia, agranulocytosis, decreased platelet aggregation, prolonged bleeding time, aplastic anaemia and haemolytic anaemia. decrease in hemoglobin levels and/or hematocrit, granulocytopenia

Eye Disorders: Corneal opacity, blurred vision, visual disturbances, papillitis and papilloedema.

Ear and Labyrinth disorders: hearing disturbances including impairment, tinnitus, and vertigo.

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

Skin and subcutaneous tissue disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, skin eruption, Stevens Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, very rarely toxic epidermal necrolysis, photosensitivity reactions (including cases in which 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 to, glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, raised serum creatinine, renal papillary necrosis and renal failure.

Reproductive system and breast disorders: Female infertility.

General disorders and administration site conditions: 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 at Website: www.mhra.gov.uk/yellowcardor search for MHRA Yellow card in the google play or Apple App store.

4.9 Overdose

Symptoms:

Symptoms include headache , nausea , vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, heartburn, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, transient changes in liver function, hypothrombinemia, apnea and metabolic acidosis. 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 the drug would be life-threatening.

Management:

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.

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. ATC code: M01AE02

Naproxen is a non-steroidal anti-inflammatory analgesic compound with 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 NSAIDs). As with other NSAIDs, however, the exact mechanism of its anti-inflammatory action is not known.

5.2 Pharmacokinetic properties

Naproxen is completely absorbed from the gastro-intestinal tract, and peak plasma levels are reached in 2 to 4 hours. Naproxen is present in the blood mainly as unchanged drug, extensively bound to plasma proteins. The plasma half-life is 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. 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

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

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 seet 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. Pharmaceutical particulars
6.1 List of excipients

lactose monohydrate

maize Starch

polyvinylpyrollidone ( povidone K 30 )

magnesium stearate (E572)

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

Opaque containers: 3 years

Blister Packs: 3 years

6.4 Special precautions for storage

Containers: Do not store above 25°C. Store in the original container.

Blister pack: Do not store above 25°C. Keep container in the outer carton.

6.5 Nature and contents of container

White polypropylene containers with LDPE closure having tamper evident seal :

1000, 500, 250, 100, 84,70, 56,42, 28, 21, 15 and 14 tablets.

Blister Strips (composed of PVC film and aluminium foil ) :

84, 70, 56, 42, 28, 21, 15 and 14 tablets.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Accord Healthcare Limited,

Sage House,

319 Pinner Road,

North Harrow,

Middlesex,

HA1 4HF,

United Kingdom

8. Marketing authorisation number(s)

PL 20075-0058

9. Date of first authorisation/renewal of the authorisation

03/09/2007

10. Date of revision of the text

06/12/2019