This information is intended for use by health professionals

1. Name of the medicinal product

Naproxen 250mg Tablets

2. Qualitative and quantitative composition

Naproxen 250mg

For excipients, see 6.1.

3. Pharmaceutical form

Tablet for oral use

4. Clinical particulars
4.1 Therapeutic indications

Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, acute gout and acute musculoskeletal disorders.

4.2 Posology and method of administration

For oral administration

To be taken preferably with or after food.

Adults:

Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis:

The usual dose is 500mg to 1g daily in two doses at 12 hour intervals.

Acute gout: The usual dose is 750mg initially followed by 250mg every eight hours until the attack has passed.

Acute musculoskeletal disorders: The usual dose is 500mg initially followed by 250mg at 6-8 hour intervals up to a maximum daily dose after the first day of 1250mg.

Elderly:

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 during NSAID therapy.

Children over 5 years:

For the treatment of juvenile rheumatoid arthritis the usual dose is 10mg/kg daily in two doses at 12 hour intervals.

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

4.3 Contraindications

Hypersensitivity to any of the constituents:

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.

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

High doses of non-steroidal anti-inflammatory drugs are contraindicated with concomitant mifamurtide

During the last trimester of pregnancy (See section 4.6 – Pregnancy and lactation).

Active or history of recurrent peptic ulcer/haemorrahage (two or more distinct episodes of proven ulceration.

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

4.4 Special warnings and precautions for use

In all patients:

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (See Section 4.2 – Posology and administration)

Caution is required in patients with haemophilia or other bleeding problems, including coagulation or platelet function disorders, due to the increased risk of gastrointestinal haemorrhage.

Infections and Infestations:

Caution should be used in patients with infections because signs and symptoms such as fever, inflammation and pain may be masked by NSAIDs.

Varicella (chickenpox) can be at the origin of serious cutaneous and soft tissue infectious complications. To date, the contributing role of NSAIDs in the worsening of varicella infections cannot be ruled out. Naproxen should be used with caution in patients, particularly children, with varicella infection, particularly if there is a possibility of secondary infection

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.

Renal and Hepatic Impairment:

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (See also section 4.3 – Contraindications).

The use of NSAIDs may result in deterioration of renal function and naproxen is eliminated mainly by urinary excretion. The dose should be kept as low as possible in patients with mild renal impairment in whom sodium and water retention, deterioration in renal function and renal failure may occur. If possible, avoid naproxen in moderate to severe renal impairment.

Chronic liver disease, including hepatic cirrhosis (especially if associated with chronic alcoholism) reduces the total plasma concentration of naproxen while increasing the concentration of the unbound drug. There is an increased risk of gastro-intestinal bleeding and fluid retention. The lowest effective dose should be used in patients with impaired hepatic function. The use of naproxen in patients with severe liver disease should be avoided.

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) however, non-selective NSAIDs are also associated with a small increased risk in thrombotic events even when used short-term in those with no cardiovascular risk factors. 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).

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), in the elderly and in patients who smoke. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly 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 ulceration, or bleeding, such as corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors, 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 under close supervision 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) and because of the potential for gastrointestinal bleeding.

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).

Skin and subcutaneous tissue disorders:

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

Naproxen should be used in caution in patients with allergic disorders

Female fertility:

Long-term use of some NSAIDs is associated with reduced female fertility which is reversible on stopping treatment. The use of naproxen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of naproxen should be considered.

At high doses in mid-cycle, naproxen can inhibit ovulation and cause the so-called luteinised unruptured follicle syndrome (See section 4.8 - Undesirable effects).

In patients on long-term therapy, there is a risk of naproxen-induced pseudoporphyria, with scar formation in light-exposed areas (see section 4.8 - Undesirable effects).

Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors should be avoided (See section 4.5 - Interactions).

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

4.5 Interaction with other medicinal products and other forms of interaction

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.

Alcohol: Concurrent use of alcohol with an NSAID can increase the risk of NSAID associated gastrointestinal side-effects, including bleeding and ulceration.

Analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs, (including low-dose aspirin), as this may, as this can increase the risk of gastrointestinal side-effects and toxicity including ulceration or haemorrhage. (See Section 4.3 - Contraindications)

Anion-exchange resins: Cholestyramine may delay the rate of absorption of naproxen.

Antibacterials, Antiepileptics: Naproxen is strongly bound to plasma proteins so that patients receiving concurrent treatment with hydantoins (such as phenytoin), or highly protein bound sulphonamides should be observed for overdosage of these drugs. Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Convulsions may occur if naproxen is given with quinolone antibiotics such as ciprofloxacin. There is a potential for an increased risk of nephrotoxicity with concomitant administration of NSAIDs and aminoglycosides.

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin and heparin (See section 4.4 – Special warnings and precautions for use).

Antidepressants: There is a potential for an increased risk of bleeding when NSAIDs and SSRIs are used concomitantly.

Antidiabetics: The hypoglycaemic effects of sulphonylureas may be enhanced with NSAIDs.

Antihypertensives: Reduced antihypertensive effect of antihypertensives, including beta-blockers, ACE inhibitors and angiotensin-II antagonists, methyldopa and vasodilator antihypertensives (e.g. hydralazine). Increased monitoring, to establish the effectiveness of antihypertensive therapy, may be necessary when given concomitantly with NSAIDs such as naproxen. There is also an increased risk of nephrotoxicity and renal impairment and of hyperkalaemia with concomitant administration of ACE inhibitors or angiotensin-II antagonists and NSAIDs.

Antiplatelet drugs: Concurrent use of antiplatlets with an NSAID (including naproxen) may increase the risk of gastrointestinal haemorrhage.

Antivirals: Ritonavir may increase the plasma concentration of NSAIDs. 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.

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

Corticosteroids: Corticosteroids (glucocorticoids), such as prednisolone, increase the risk of gastro-intestinal bleeding and ulceration with NSAIDs. Naproxen can have a steroid-sparing effect resulting in an increase in the level of concomitant corticosteroid, so that the dose of corticosteroid may be reduced. (See section 4.4 – Special warnings and precautions for use).

Cytotoxic drugs: Decreased elimination thereby enhancing the toxicity of methotrexate.

Diuretics: NSAIDS may reduce the antihypertensive effect of diuretics. Increased monitoring may be necessary when administered concomitantly.(See section 4.4 special warnings and precautions for use).

Reduced diuretic effect. The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. The risk of hyperkalaemia may be increased with concomitant administration of NSAIDs and potassium-sparing diuretics. The risk of nephrotoxicity may be increased if diuretics are given concurrently.

Immunosuppressants: Increased risk of nephrotoxicity if ciclosporin or tacrolimus given concurrently.

Lithium: Decreased elimination of lithium.

Mifamurtide: High doses of non-steroidal anti-inflammatory drugs are contraindicated with concomitant mifamurtide.

Mifepristone: Naproxen and other NSAIDs should be avoided for 8 - 12 days after mifepristone is administered as NSAIDs can reduce the effect of mifepristone.

Oxipentifylline (Pentoxifylline): The concurrent use of oxipentoxifylline with an NSAID may increase the risk of gastrointestinal bleeding and ulceration.

Penicillamine:There is a potential for an increased risk of nephrotoxicity when NSAIDs (including naproxen) and penicillamine are used concomitantly

Probenecid: Naproxen plasma levels are increased and its plasma half-life extended by the concurrent administration of probenecid.

4.6 Pregnancy and lactation

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, naproxen should not be given unless clearly necessary. If naproxen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

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

- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the neonate, at the end of pregnancy, to:

- possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

- inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, naproxen is contraindicated during the third trimester of pregnancy.

Lactation:

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

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Blood and lymphatic system disorders: Naproxen decreases platelet aggregation and prolongs the bleeding time. Thrombocytopenia, agranulocytosis, granulocytopenia, neutropenia, aplastic anaemia and haemolytic anaemia may occur rarely. Eosinophilia can occur rarely.

Immune system disorders: Anaphylactoid reaction and pyrexia are side effects of naproxen. Anaphylactic shock and rhinitis are side effects of NSAIDs including naproxen. Other hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm, eosinophilic pneumonia, or dyspnoea or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Metabolism and nutrition disorders: Cases of hyponatraemia have been reported. There is also a potential for hyporeninaemic hypoaldosteronism to occur. Hyperkalaemia

Psychiatric disorders: Nervousness, nightmares insomnia, depression, confusion, hallucinations

Nervous system disorders: optic neuritis headaches, paraesthesia, 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 or disorientation (See section 4.4), dizziness, and drowsiness, inability to concentrate and cognitive dysfunction have been reported. Peripheral neuropathy has been reported with the use of naproxen.

Eye disorders: Visual disturbances such as blurred vision, Papilloedema can occur as a rare side effect of naproxen. There is a potential for corneal opacity to occur rarely.

Ear and labyrinth disorders: Tinnitus, vertigo, and hearing impairment

Cardiac disorders: Naproxen has the potential to induce or exacerbate congestive heart failure. Oedema has been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

Vascular disorders: Vasculitis. Hypertension can occur rarely.

Respiratory, thoracic and mediastinal disorders: Pneumonitis has been reported to occur while using naproxen. Alveolitis,

Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Gastrointestinal erosion and/ or ulceration, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see Section 4.4). Nausea, vomiting, diarrhoea flatulence, constipation, dyspepsia, abdominal pain, heartburn, salivery gland enlargement, melaena, haematemesis, ulcerative stomatitis, induction or exacerbation of colitis has been reported, and exacerbation of Crohn's disease (See section 4.4 Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis and pancreatitis have been observed. Systemic as well as local effects of NSAIDs contribute to gastro-intestinal damage: taking oral formulations with milk or food or using enteric coated formulations, or changing the route of administration may only partially reduce symptoms such as dyspepsia.

Hepatobilary disorders: Abnormal liver function, jaundice, fatal hepatitis. Cholestatic hepatitis and cholestatic jaundice can occur rarely as side effects of naproxen.

Skin and subcutaneous tissue disorders: Bullous reactions including Steven's Johnson syndrome and toxic epidermal necrolysis (TEN) (very rare). Lichen planus, fixed drug eruption, photosensitivity and alopecia have also been reported in patients receiving naproxen. Erythema nodosum and cutaneous vasculitis have also been reported as naproxen side effects.Pseudoporphyria

Renal and urinary disorders: Nephrotoxicity in various forms, including haematuria, interstitial nephritis, nephrotic syndrome, renal impairment or failure, renal papillary necrosis and fluid retention. Interstitial fibrosis has been reported. Rarely, papillary necrosis or interstitial fibrosis associated with NSAIDs can lead to renal failure.

Reproductive system and breast disorders: In women, there is a potential for menstrual disturbances to occur. In men, cases of impotence have been reported. Reversible infertility has also been reported

General disorders and administration site conditions: rarely encountered side effects include, malaise and fatigue (please refer to section 4.4 - Special warnings and precautions for use).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms:

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

Therapeutic measures:

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered.

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Naproxen is a derivative of propionic acid with anti-inflammatory, analgesic and anti-pyretic properties.

The mode of action of naproxen is unclear but its actions are due in part to its ability to inhibit prostaglandin synthesis.

5.2 Pharmacokinetic properties

Naproxen is completely absorbed when taken by mouth. Plasma levels are proportional to dosage up to 500mg. Peak plasma concentrations occur within two to four hours. It is 99% bound to plasma protein. A large proportion reaches the synovial fluid and membrane.

Naproxen is mainly excreted in the urine as the glucuronide conjugate and the inactive metabolite 6-0-desmethyl naproxen. The half-life is 12 to 15 hours.

Naproxen crosses the placenta and is excreted in breast milk.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to those already included in the other sections.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose

Maize starch

Povidone

Sodium starch glycollate

Magnesium stearate

Purified water

Yellow lake CLF (3076):

Quinoline yellow aluminium lake (E104)

Iron oxide (E172)

6.2 Incompatibilities

None

6.3 Shelf life

Three years in PVC strips

Three years in polyethylene/polypropylene containers

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

Blister strips in multiples of 10 or 14 tablets in 250µ PVC sealed with 20µ aluminium foil, in cartons.

Polypropylene or polyethylene tablet containers with tamper evident seals.

Pack size: 30, 60, 100, 250, 1000.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing authorisation number(s)

PL 29831/0150

9. Date of first authorisation/renewal of the authorisation

6th November 2007

10. Date of revision of the text

02/08/2018