SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Naproxen 250 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 mg of naproxen.

Excipients with known effect:

Each Naproxen 250 mg tablet contains 60.83 mg lactose (as lactose monohydrate). For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

Yellow coloured, mottled, biconvex, beveled edged, round shape (diameter 10.5mm), uncoated tablets debossed with ‘T’ & ‘18’ on either side of breakline on one side and other side plain. The tablet can be divided into two equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Adults:

Treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis), ankylosing spondylitis, acute gout, acute musculo skeletal 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).

Adults

Rheumatoid arthritis, osteoarthritis and ankylosing spondylitis

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 nighttime pain/or morning stiffness.

b.    In patients being switched to Naproxen from a high dose of another antirheumatic compound.

c.    In osteoarthrosis where pain is the predominant symptom.

Acute gout

Initial dose of 750 mg, then 8 hours later 500 mg, after this 250 mg every 8 hours until the crisis has passed.

Acute musculoskeletal disorders and dysmenorrhoea

500mg initially followed by 250mg at 6-8 hour intervals as needed, with a maximum daily dose after the first day of 1250mg.

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 Naproxen 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 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.

Paediatric population (over 5 year, above 25kg weight)

For juvenile rheumatoid arthritis: 10mg/kg/day taken in 2 doses at 12hour intervals.

Naproxen is 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. 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

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

Hypersensitivity to naproxen, naproxen sodium, or to any of the excipients listed in section 6.1. Since the potential exists for crosssensitivity reactions, Naproxen should not be given to patients in whom aspirin or other nonsteroidal antiinflammatory/ analgesic drugs induce the syndrome of asthma, rhinitis, nasal polyps or urticaria. These reactions have the potential of being fatal. Severe anaphylactic like reactions to naproxen have been reported in such patients.

-    Severe renal insufficiency.

-    Severe heart failure.

-    Severe hepatic failure.

Naproxen is contraindicated during the last trimester of pregnancy (see Section 4.6).

4.4 Special warnings and precautions for use

If use is made of the lowest possible effective dose for the shortest period needed to fight the symptoms, the side effects can be kept to a minimum. (see section 4.2, and gastro-intestinal and cardiovascular risks below). Naproxen should be administered under strict medical supervision to patients with a history of gastro-intestinal tract disorders and to patients with coagulation disorders , as well as those on long-term NSAIDs..

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

As with other nonsteroidal antiinflammatory 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 nonsteroidal Antiinflammatory drugs. Cross reactivity has been reported.

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).

Naproxen reduces the platelet aggregation and prolongs the bleeding time.

Patients using anti-coagulation products should be carefully monitored during the use of naproxen.

Patients who use coumarin derivatives or heparin in addition to naproxen are at an increased risk for bleedings. In that case the benefits should be carefully weighed against the risks. In any case concomitant use of naproxen and a high dose of heparin (or derivatives thereof) is not recommended.

Severe gastro-intestinal side effects can occur in patients who use prostaglandin -synthetase inhibiting products. The risk of the occurrence of gastro-intestinal ulcers or bleedings increases with the duration of use and the dose of naproxen. This risk is not limited to a specific patient population, but elderly patients and weakened patients show a poorer tolerance for gastro-intestinal ulcerations or bleedings than others. The most fatal gastrointestinal effects that were ascribed to prostaglandin synthetase inhibiting products occurred in this population.

Hypersensitivity reactions can occur in patients sensitive to this.

Anaphylactic (anaphylactoid) reactions can occur in patients with and without a history of hypersensitivity or in patients who have not been exposed to acetyl salicylic acid, naproxen (sodium) and other NSAID’s before. They can occur in patients with angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and a history of nasal polyps. Anaphylactoid reactions can, just like anaphylaxis, have a fatal result.

In a few patients a mild peripheral oedema has been reported.

No sodium retention has been observed with metabolic studies, but it cannot be ruled out that certain patients with (presumably) abnormal cardiac functions are at a greater risk of showing this side effect symptom.

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.

In patients with renal insufficiency naproxen must be administered with extreme caution, especially if it concerns a long-term treatment. Also sufficient diuresis must be taken care of.

In case of a reduced renal perfusion, it is recommended to monitor the renal function before and during the treatment with naproxen. Severe renal insufficiency is a contraindication, see 4.3 "Contra-indications".

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, angiotensinII receptor antagonists and older people. Renal function should be monitored in these patients (see also Section 4.3).

Caution is also needed in patients with hepatic insufficiency.

Caution is recommended when high doses of naproxen are administered to elderly patients, as there are indications that the quantity of non-protein bound naproxen increases in these patients.

As naproxen has an anti-inflammatory, analgesic and antipyretic effect certain infection symptoms may therefore be masked.

In rare cases ocular abnormalities (see 4.8 "Undesirable effects") have been reported in users of NSAIDs, which includes naproxen, although a causal connection could not be established. Patients, in whom visual disorders occur during the treatment with naproxen, should have an ophthalmological examination.

If the skin becomes delicate, if blisters or other symptoms occur indicating pseudoporphyria, the treatment must be discontinued and the patient should be carefully monitored.

When a corticosteroid is replaced by naproxen and partial or complete substitution takes place, the usual precautions should be applied that are considered for the discontinuation of a corticosteroid treatment.

The administration of naproxen is not recommended for patients under the age of six years.

Cardiovascular and cerebrovascular effects

Patients with a history of hypertension and/or a mild or moderate form of congestive heart failure will have to be carefully monitored and advised, as fluid retention and oedema formation has been reported in association with a therapy with NSAIDs.

Information from clinical studies and epidemiological data suggest that the use of some NSAIDs (especially in high doses and with long-term use) can be associated with a slightly increased risk of thrombosis in the arteries (for instance myocardial infarction or stroke). Epidemiological studies suggest that naproxen in low doses (1000 mg per day) can be associated with a lower risk, some risk cannot be ruled out.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic cardiac disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with naproxen after careful consideration. The same consideration should be made before a long-term treatment is started in patients with risk factors for cardiovascular disease (for instance hypertension, hyperlipidaemia, diabetes mellitus and smoking).

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems, such as galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption should not use this medicinal product.

The concomitant use of naproxen and other NSAIDs, including selective COX-2 inhibitors, should be avoided.

Elderly patients: Elderly patients more frequently experience side effects of NSAIDs, in particular gastro-intestinal bleeding and perforation, which can be fatal (see section 4.2).

Gastro-intestinal bleeding, ulceration and perforation: Gastro-intestinal bleeding, ulceration and perforation, which can be fatal, have been reported with the use of all NSAIDs at any time during the treatment, with or without warning symptoms or the prior occurrence of severe gastro-intestinal side effects.

The risk of gastro-intestinal bleeding, ulceration and perforation is greater with higher doses, the prior occurrence of ulceration, in particular if complicated by bleeding and perforation (see section 4.3) and in elderly patients. These patients should start the treatment with the lowest available dosage. Combination treatment with protective products (for example misoprostol or proton pump inhibitors) should be considered in these patients as well as in patients who concomitantly need low doses of acetyl salicylic acid or other medicinal products that probably increase the gastro-intestinal risk (see section 4.5).

Patients, who previously had a problem with gastro-intestinal toxicity, in particular elderly patients, should report any unusual abdominal symptoms (especially bleeding), in particular at the beginning of the treatment. Caution is needed in patients who are concomitantly treated with medicinal products, which may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors and products that counteract the platelet aggregation, such as acetyl salicylic acid (see section 4.5).

When gastro-intestinal bleeding or ulceration occurs in patients who are receiving naproxen, the treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of gastro-intestinal diseases (ulcerative colitis, Crohn’s disease) as these conditions can worsen (see section 4.8).

Caution is needed in patients with a history of hypertension and/or heart failure, because fluid retention and oedema have been reported in connection with NSAID therapy.

Severe skin reactions, of which some fatal, including exfoliative dermatitis, Stevens-Johnson’s syndrome and toxic epidermal necrolysis have very rarely been reported in connection with the use of NSAIDs (see section 4.8). Patients appear to have the greatest risk of these reactions at the beginning of the treatment: in the majority of the cases the reaction started in the first month of the treatment. Treatment with naproxen should be discontinued with the first symptoms of a skin rash, mucosal laesions or any other sign of hypersensitivity.

The use of naproxen may reduce the fertility of the woman and in not recommended for women who want to become pregnant. In women who have difficulty becoming pregnant or who are undergoing fertility examinations should be considered discontinuing the use of naproxen.

In exceptional cases varicella can cause severe infectious complications of the skin and soft tissues. To this day the contributing role of NSAIDs in the potentiation of these infections cannot be ruled out. It is therefore recommended to avoid the use of naproxen in case of varicella.

Long-term use of any pain medication for headache may worsen the existing headache. If this situation occurs or is suspected, a doctor should be consulted and the treatment should be discontinued. In patients, who have frequently or daily headaches, despite (or as a result of) the regular use of medications for headaches, the diagnosis headache as a result of excessive use of medication should be taken into account.

4.5 Interaction with other medicinal products and other forms of interaction

The following combinations should be avoided with naproxen:

Anticoagulants

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

Methotrexate

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

Ticlopidine

NSAIDs should not be combined with ticlopidine due to the additional inhibition of thrombocyte function.

NSAIDs and Aspirin

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).

Mifepristone

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

The following combinations with naproxen may require dosage adjustment or specific monitoring of the patient:

Lithium

Naproxen decreases renal clearance of lithium. This can cause lithium concentrations in serum to rise by up to 40%. Because of lithium's very low therapeutic index, the combination of lithium and NSAIDs should be avoided unless frequent monitoring of serum lithium levels can be implemented and any reductions can be made to the lithium dose.

Ciclosporin

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

Probenecid

Probenecid given concurrently increases naproxen plasma levels and extends its halflife considerably.

Diuretics and other antihypertensive drugs

Caution is advised when Naproxen is coadministered 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.

Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of antihypertensives.

ACE inhibitors and angiotensin II antagonists

Concomitant use of NSAIDs with ACE inhibitors or angiotensin-II receptor antagonists may increase the risk of renal impairment, especially in patients with preexisting poor renal function (See Section 4.4).

There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Clopidogrel

Experimental studies have found that clopidrogrel increases naproxen-induced gastrointestinal blood loss. This is likely to apply to all NSAIDs.

Corticosteroids

As with all NSAIDs, caution should be taken when coadministering with corticosteroids because of the increased risk of gastrointestinal ulceration or bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs)

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

Hydantoins, sulfonamides or sulfonylureas

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 nonsteroidal agents of this class.

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.

Quinolone antibiotics

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

Cardiac glycosides

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

Zidovudine and Ibuprofen

There is an increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma

in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

The clinical significance of the following combinations with naproxen has not yet been established:

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

4.6 Fertility, pregnancy and lactation

Fertility

There have been some indications that products that inhibit the cyclo-oxygenase/ prostaglandin synthesis reduce the fertility of women by having an effect on the ovulation. This is reversible by discontinuing the treatment.

Pregnancy

Inhibition of the prostaglandin synthesis may negatively affect the pregnancy and/or the embryonal/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformations and gastroschisis after the use of prostaglandin synthesis inhibitors in the early stages of the pregnancy. The absolute risk of cardiovascular malformation was increased from less than 1 % to approximately 1.5%. It is accepted that the risk increases with the dose and the duration of the treatment. The administration of prostaglandin synthesis inhibitors in animals resulted in an increased pre- and post-implantation loss and embryo-foetal lethality. In addition an increased incidence of various malformations, including cardiovascular ones, have been reported in animals who received a prostaglandin synthesis inhibitor during the period of organogenesis. Naproxen should not be used during the first and second trimester of the pregnancy unless this is absolutely necessary. If naproxen is used by a woman who is trying to become pregnant, or in the first or second trimester of the pregnancy, the dose should be kept as low as possible and the treatment should be as short as possible.

During the third trimester of the pregnancy all prostaglandin synthesis inhibitors can

expose the foetus to:

-    cardiopulmonary toxicity (premature closing of the ductus arteriosus and pulmonary hypertension);

-    renal dysfunction, which may develop into renal failure with oligohydroamnios; At the end of the pregnancy the mother and neonate to:

-    possible prolonging of the bleeding time, an anti-aggregation effect, which may even occur with very low doses.

-    inhibition of the contraction of the uterus resulting in a delayed or prolonged delivery.

As a result thereof naproxen is contra-indicated during the third trimester of the pregnancy.

Breast-feeding

Naproxen has been found in the milk of lactating women. The use of Naproxen should be avoided in patients who are breastfeeding.

4.7 Effects on ability to drive and use machines

Naproxen can cause drowsiness and dizziness. In certain cases this may have consequences for the ability to drive a motor vehicle and/or operate dangerous machines.

4.8 Undesirable effects

During the medication with naproxen the following side effects and symptoms, which did not lead to the discontinuation of the therapy in all cases, were observed in various gradation and frequencies.

Frequencies have been defined as:

Very common (>1/10)

Common (>1/100, <1/10)

Uncommon (>1/1.000, <1/100)

Rarely (>1/10000, <1/1000)

Very rarely (<1/10.000)

Unknown (cannot be determined with the available data)

Organ system	Side effect Frequency
	Very common	Common	Uncommon	Rarely	Very rarely	Unknown
Blood and lymphatic system disorders		Ecchymoses, reduced aggregation ability of the platelets, prolonged bleeding time.		Reduction of the haemoglobin level and/or haematocrit, aplastic or haemolytic anaemia, thrombocytopen ia, neutropenia, granulocytopeni a,

				agranulocytosis, eosinophilia, leukopenia.
Immune system disorders				Anaphylactic reaction.		Allergic reactions
Nutrition and metabolism disorders				Reduced appetite.
Psychiatric disorders				Insomnia, nervousness, euphoria, abnormal dreaming, reduced ability to concentrate, cognitive dysfunction, mild depression, hallucinations..
Nervous system disorders		Headache, dizziness, drowsiness, light headedness.		Aseptic meningitis, angioneurotic oedema, convulsions.
Ocular disorders			Blurred vision	Corneal clouding, papillitis, retrobulbar optic neuritis, papilloedema
Equilibrium and ear disorders		Ringing in the ear.	Vertigo, hearing disorders
Cardiac disorders			Palpitations.	Elevated blood pressure, Heart failure
Vascular disorders				Vasculitis.
Respiratory system, chest and mediastinum disorders		Dyspnoea		Pulmonary oedema, eosinophilic pneumonitis, asthma.
Gastro intestinal system		Heartburn,nau sea, feeling of being unwell	Vomiting, blood loss from the	Perforation of the gastrointestinal tract,		gastritis, obstruction, exacerbation

disorders		in the epigastric area or abdomen, constipation.	gastrointestinal tract, peptic ulcer, stomatitis (rarely ulcerative), thirst, dyspepsia, diarrhoea.	non-peptic ulcers, colitis, oesophagitis, haematemesis, pancreatitis, feeling of dry mouth, throat irritation.		of ulcerative colitis and Crohn's disease'
Liver and biliary disorders				Increase of the transaminases or of the alkaline phosphatases, increase of the bilirubin level, icterus, hepatitis, including a few cases with fatal results.
Skin and subcutaneou s skin disorders		Skin eruptions, pruritus.	Purpura.	Alopecia, urticaria, erythema multiforme, light hypersensitivity reactions including porphyria cutanea tarda, porphyria cutanea tarda--like reactions and epidermolysis bullosa, epidermal necrolysis, erythema nodosum, lichen planus, pustular reactions, "fixed drug eruptions", Stevens-Johnson syndrome.
Musculoskel etal and connective tissue				Muscle weakness		myalgia, SLE(Systemi c lupus erythematosu

disorders						s)
Renal and urinary tract disorders				Pollakisuria, proteinuria, glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, renal insufficiency, haematuria, increased serum creatinine, hyperkalaemia.
Reproductiv e system and breast disorders:						Female infertility
General disorders and administrati on site disorders		Peripheral oedema.	Perspiration.	Fatigue, temperature reduction, pyrexia.		malaise

Oedema formation, hypertension and heart failure have been reported in association with treatment with an NSAID.

Information from clinical studies as well as epidemiological data suggest that the use of naproxen, especially in high doses and with long-term use, can be associated with a slightly increased risk of thrombosis in the arteries (for instance myocardial infarction or stroke).

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: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdose can consist of nausea, vomiting, pain in the gastric region, drowsiness, dizziness, disorientation, diarrhoea, gastric bleeding, convulsions (rarely), transient changes in hepatic functions, hypothrombinemia, renal failure, apnoea and metabolic acidosis.

In first instance the treatment consists of the prevention of the absorption through lavage and then drinking water or fruit drink with activated charcoal (adsorbent) and sodium sulphate (laxative). With large quantities gastric lavage is indicated, leaving behind activated charcoal and sodium sulphate.

The acid base should be carefully monitored in connection with the possible occurrence of a severe metabolic acidosis.

Further treatment is supportive and symptomatic.

Hemodialysis does not reduce the plasma concentration of naproxen, due to the high protein binding.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, nonsteroids.Propionic acid derivatives.ATC code: M01AE02

Mechanism of action

Naproxen is a nonsteroidal anti-inflammatory analgesic compound with antipyretic properties as has been demonstrated in classical animal test systems. Naproxen exhibits its antiinflammatory

effect even in adrenalectomised animals, indicating that its action is not mediated through the pituitaryadrenal 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

Absorption

The absorption from the gastro-intestinal tract after oral administration is practically complete and takes place rather rapidly.

Distribution

The protein binding of naproxen in normal doses is greater than 99%.

Biotransformation 30% of naproxen is converted into 6-O-desmethyl naproxen in the liver.

Elimination

With increasing dosage the urinary excretion is faster than could be expected based on linear processes. The plasma half life is approximately 11 - 15 hours. Approximately 95% of the administered dose is excreted with the urine, primarily in the form of naproxen, 6-O-desmethyl naproxen or conjugated forms of the mentioned substances.

5.3 Preclinical safety data

Carcinogenicity

Naproxen was administered with food to SpragueDawley 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 does 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 Sodium starch glycolate

Povidone (E1201)

Yellow iron oxide (E172) Magnesium stearate (E470b)

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

4 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Naproxen tablets are available in clear PVC/ PE/ PVdC - aluminium foil blister packs and white opaque HDPE-container closed with white opaque polypropylene stock ribbed closure with wad having induction sealing liner.

Package sizes:

Blister packs: 7, 10, 12, 15, 16, 20, 24, 25, 28, 30, 40, 50, 56, 60, 90, 98, 100, 250 and 500 tablets

HDPE _ packs:

30, 100, 250 and 1000 tablets Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

Millpharm Limited

Ares Block

Odyssey Business Park West End Road Ruislip HA46QD United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 16363/0479

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/05/2016

10    DATE OF REVISION OF THE TEXT

04/05/2016