4.1. Therapeutic indications

Adults

Naproxen Oral Suspension is indicated for the symptomatic treatment of

- pain and inflammation in:

• rheumatoid arthritis, ankylosing spondylitis and acute attacks of osteoarthrosis and spondylarthrosis

• acute gout

• inflammatory rheumatic diseases of soft tissues

• painful swelling or inflammation after musculoskeletal injuries

- pain in primary dysmenorrhoea

Paediatric population

Naproxen is indicated for juvenile idiopathic arthritis in children from 2 years of age and older.

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 the symptoms.

The medicinal product contains a 8mL graduated oral syringe with graduations of 0.1mL.

Adults up to 65 years of age

The recommended dose range is from 500mg to not more than 1,000mg naproxen per day (10–20mL).

Dosage should be individually adjusted to the clinical condition. A single dose of 1,000mg naproxen (20mL) should not be exceeded.

Symptomatic treatment of painful swelling or inflammation after musculoskeletal injuries

The recommended initial dose is 500mg (10mL); additional doses of 250mg (5mL) may be taken every 6–8 hours as needed. The daily dose should not exceed 1,000mg (20mL).

Symptomatic treatment of pain and inflammation in rheumatoid arthritis, ankylosing spondylitis and acute attacks of osteoarthrosis and spondylarthrosis as well as in inflammatory rheumatic diseases of soft tissues

The daily dose is usually 10–15mL of Naproxen Oral Suspension (equivalent to 500–750 mg naproxen).

At the start of therapy, during phases of acute inflammation or when switching from another high-dose NSAID to Naproxen, the recommended daily dose is 15mL (equivalent to 750mg naproxen), administered as two divided doses per day (10mL of Naproxen Oral Suspension in the morning and 5mL in the evening, or vice versa) or as a single dose (either in the morning or in the evening).

In individual cases, the daily dose may be increased to 20mL (equivalent to 1,000mg naproxen).

The maintenance dose is 10mL of Naproxen Oral Suspension (equivalent to 500mg naproxen) per day, which may be administered either in two divided doses (5mL in the morning and 5mL in the evening) or as a single dose (either in the morning or in the evening).

Symptomatic treatment of pain and inflammation in acute gout

The recommended initial dose is 750mg (15mL), followed by 250mg (5mL) every 8 hours – until the attack is over. (In this case, exceeding the maximum daily dose of 1,000mg is justified on this single occasion.)

Symptomatic treatment of pain in primary dysmenorrhoea

The recommended initial dose is 500mg (10mL); additional doses of 250mg (5mL) may be taken every 6–8 hours. A daily dose of 1,000mg (20mL) should not be exceeded.

Paediatric population (from 2 years of age and older)

For juvenile idiopathic arthritis: 10mg naproxen/kg of body weight per day which corresponds to a daily dose of 0.2mL Naproxen Oral Suspension per kilogram of body weight, administered in two divided doses (single dose 0.1mL/kg of body weight). The daily dose for adolescents should not exceed 20mL (1,000mg).

Naproxen is not recommended in children under 2 years of age because there is no adequate experience.

Naproxen is not recommended for use in any indication other than juvenile idiopathic arthritis in children and adolescents under 18 years of age.

Duration of treatment

The duration of use is decided by the treating physician.

For rheumatic diseases, it may be necessary to take Naproxen over a prolonged period.

In primary dysmenorrhoea the treatment duration depends on the respective symptomology. However, the treatment with Naproxen should not exceed a few days.

Special patient populations

Elderly (over 65 years of age)

Older patients 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. Older patients require particularly careful medical monitoring: Overdose as a result of reduced elimination and an increased proportion of free – not bound to plasma protein – drug should be expected (see section 4.4).

Hepatic impairment

Patients with liver disease and hypoproteinaemia are also at risk of naproxen overdose as a result of an increased proportion of free – not bound to plasma protein – drug. These patients should be given the lowest dose that is still effective and be monitored. Naproxen is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).

Renal impairment

Dose reduction should be considered in patients with renal impairment whose creatinine clearance is greater than 30mL per minute in order to avoid accumulation of metabolites.

Naproxen should not be administered to patients whose creatinine clearance is less than 30mL per minute (see sections 4.3 and 4.4).

Method of administration

For oral use.

Naproxen should be taken with sufficient liquid.

Shake the bottle vigorously before use.

In acute pain, naproxen starts to act earlier when taken on an empty stomach.

Patients with sensitive stomach should take Naproxen during meals.

4.3. Contraindications

Naproxen must not be taken in any of the following conditions:

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• history of asthma attacks, angioedema, skin reactions or acute rhinitis after taking acetylsalicylic acid or any other non-steroidal anti-inflammatory drugs (NSAIDs).

• blood-formation disturbances

• severe cardiac insufficiency

• active peptic ulcer or bleeding

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

• history of gastrointestinal bleeding or perforation, related to previous NSAID therapy

• cerebral haemorrhage (cerebrovascular bleeding)

• acute haemorrhage

• severe hepatic impairment

• severe renal impairment (creatinine clearance less than 30mL/min)

• 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 the symptoms (see section 4.2, and GI and cardiovascular risks below).

Co-administration of naproxen with other non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2-selective inhibitors should be avoided.

Naproxen must be stopped immediately in case of gastrointestinal bleeding or visual disturbances or hearing impairment.

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 because fluid retention and oedema have been reported in association with NSAID therapy.

Clinical studies and epidemiological data suggest that the use of some NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Although data from epidemiological studies suggest that naproxen (1,000mg/day) may be associated with a lower risk, some of such risk can, however, not be completely 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 also be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Respiratory tract

Particular caution (careful risk/benefit assessment) is necessary in patients with asthma and allergic diseases such as hay fever, chronic swelling of the nasal mucosa, angioedema, urticaria (including a history thereof) or chronic obstructive airway disease because bronchospasm (asthma attack) may be triggered. This applies especially if other NSAIDs have previously caused this reaction. If this is the case, Naproxen must not be administered (see section 4.3).

Gastrointestinal tract

Gastrointestinal 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 gastrointestinal 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 older patients. These patient groups should commence treatment with the lowest dose available (see section 4.2).

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant treatment with low-dose acetylsalicylic acid or with other drugs that may increase gastrointestinal risk (see below and section 4.5).

Patients with a history of gastrointestinal toxicity – particularly when older – should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.

When gastrointestinal bleeding or ulceration occurs during naproxen therapy, the treatment must be stopped.

Particular caution should be exercised in patients receiving concomitant medication that might increase the risk of ulceration and bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or antiplatelet agents such as acetylsalicylic acid (see section 4.5).

NSAIDs should only be given with caution to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

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.

Kidney, urogenital tract

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.

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 the older patients. Renal function should be monitored in these patients (see also section 4.3).

As naproxen and its metabolites are excreted to a large extent (95%) in the urine via glomerular filtration, naproxen should be used with great caution in patients with renal impairment (whose creatinine clearance is greater than 30mL per minute). In addition, monitoring of serum creatinine and/or creatinine clearance is advised in these patients.

Certain patients, specifically those with compromised renal blood flow, such as in extracellular fluid volume depletion, liver disease, sodium retention, congestive heart failure and pre-existing renal disease, should have their renal function assessed before and during naproxen therapy.

Older patients with presumably impaired renal function would fall within this category, as would patients receiving diuretic therapy. A reduction in the daily dose should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.

Careful monitoring is recommended also because of possible changes in the water and electrolyte balance immediately after major surgery.

Severe cutaneous adverse reactions (SCARs)

Exfoliative dermatitis, and Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported post-marketing in association with Naproxen Oral Suspension treatment (see section 4.8). If signs and symptoms suggestive of these reactions appear, Naproxen Oral Suspension should be withdrawn immediately. If the patient has developed exfoliative dermatitis, or SJS, or TEN or DRESS with the use of Naproxen Oral Suspension, treatment with Naproxen Oral Suspension must not be restarted and should be permanently discontinued.

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 prior exposure to acetylsalicylic acid, other NSAIDs or naproxen-containing medicinal products putting them at risk of such reactions. They may also occur in patients with a history of angioedema, bronchospastic reactions (e.g. asthma), rhinitis or nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Bronchospasm may be precipitated in patients suffering from or with a history of asthma, allergic diseases or hypersensitivity to acetylsalicylic acid (see section 4.3).

Eyes

Studies have not shown any ocular changes attributable to naproxen administration. In rare cases, ocular side effects such as papillitis, retrobulbar optic neuritis and papilloedema have been reported in users of NSAIDs including naproxen, although a causal relationship could not be established. Therefore, patients who develop visual disturbances during treatment with naproxen should have an ophthalmological examination.

Uterus

Caution should be exercised in women with abnormally heavy menstrual bleeding (e.g. menorrhagia, metrorrhagia).

Autoimmune disorders

Caution should also be exercised in patients with systemic lupus erythematosus and other autoimmune disorders – there have been reports of aseptic meningitis and renal impairment.

Porphyria

In patients with inducible porphyria, naproxen should only be used after very careful risk/benefit assessment.

Elderly (over 65 years of age)

Elderly patients show an increased incidence of adverse reactions to NSAIDs, particularly of gastrointestinal bleeding and perforation, which may have a fatal outcome (see sections 4.2 and 4.8).

Liver

As with other NSAIDs, one or more liver function tests may show elevated readings, which would be the result of hypersensitivity rather than toxicity. Severe hepatic reactions including jaundice and hepatitis – some cases have been fatal – have been reported with naproxen as with other NSAIDs. Cross-reactions have been reported.

General precautions

Persistence of underlying disease

As a result of its pharmacodynamic properties, naproxen – like other NSAIDs – might mask an underlying disease by its analgesic, anti-pyretic and anti-inflammatory effects. Patients should be instructed to seek medical advice immediately in case of persistence or worsening of symptoms such as pain or other signs of inflammation, e.g. in case of worsening of overall well-being or development of fever during therapy.

Analgesic-induced headache

Inappropriate prolonged high-dose use of analgesics may give rise to headaches that must not be treated with increased doses of this medicinal product. Patients should be informed accordingly as appropriate.

Analgesic nephropathy

Habitual use of analgesics may – especially if multiple analgesic drugs are used in combination – lead to permanent kidney damage with the risk of renal failure. Patients should be informed accordingly as appropriate.

Clinical monitoring

All patients receiving long-term and/or high-dose treatment should have periodic blood counts, as well as hepatic and renal function tests. This applies particularly to patients with hepatic impairment, cardiac insufficiency, high blood pressure or kidney damage.

When diabetics treated with hypoglycaemic sulphonylurea derivatives are additionally given naproxen, blood glucose should be monitored particularly carefully to avoid missing possibly increased blood glucose reduction.

Patients receiving concomitant anticoagulant therapy are also recommended to have their clotting status monitored; the potassium concentration should be monitored (in patients taking potassium-sparing diuretics); patients taking lithium should have their lithium levels monitored, and those taking cardiac glycosides should have cardiac glycoside concentrations monitored (see section 4.5).

Interference with laboratory tests

• Increase in transaminases, alkaline phosphatase, serum potassium, urea

• Decrease in haemoglobin, haematocrit, serum calcium, creatinine clearance

• Bleeding time: It should be kept in mind that naproxen reversibly decreases platelet aggregation and prolongs bleeding time during treatment with naproxen and for up to 4 days thereafter.

• Possible interferences with 17-ketogenic steroids in adrenal function tests and 5-hydroxyindoleacetic acid in urine tests: It is recommended that naproxen be temporarily discontinued at least 72 hours before such tests are performed.

Information on excipients

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. 1 mL contains 300mg sucrose (sugar). This should be taken into account in patients with diabetes mellitus. May be harmful to the teeth.

Sorbitol

1mL of Naproxen Oral Suspension contains 90 mg sorbitol. Patients with rare hereditary problems of fructose intolerance should not take/be given this medicinal product.

Sodium

This medicinal product contains 9.2mg sodium per mL, equivalent to 0.46 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Methyl parahydroxybenzoate

May cause allergic reactions (possibly delayed).

4.5. Interaction with other medicinal products and other forms of interaction

Combinations that are not recommended:

Combination of naproxen with

Possible reactions

Other NSAIDs including salicylates and COX-2 inhibitors

Increased risk of side effects, particularly gastrointestinal bleeding risk (combination is not recommended, 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.

Corticosteroids

Increased risk of gastrointestinal ulceration or bleeding (combination is not recommended)

Antiplatelet drugs

Increased risk of gastrointestinal bleeding (combination is not recommended)

Anticoagulants

NSAIDs may increase the effect of anticoagulants - increased bleeding risk is possible (monitoring of clotting status is recommended as appropriate)

Lithium

Increase in lithium blood level (monitoring and, if necessary, dose adjustment is recommended)

Tacrolimus

Renal failure (combination should be avoided)

Alcohol

Increased risk of occurrence and exacerbation of gastrointestinal bleeding (combination should be avoided)

Mifepristone

Concomitant use of naproxen with mifepristone should be avoided because of a theoretical risk that prostaglandin synthetase inhibitors may decrease the efficacy of mifepristone.

Combinations where caution should be exercised:

Combination of naproxen with

Possible reactions

Cardiac glycosides

Increase in their blood levels (appropriate monitoring and, if necessary, dose adjustment is recommended)

Quinolones

Convulsions have been reported (very rarely)

Sulphonamides

Affect naproxen plasma levels

Zidovudine

Increased risk of haematotoxicity as a result of increased plasma levels of zidovudine

Phenytoin

Possible increase in phenytoin blood level (appropriate monitoring and, if necessary, dose adjustment is recommended)

Selective serotonin re-uptake inhibitors

Increased risk of gastrointestinal bleeding

Probenecid

Sulphinpyrazone

Delayed excretion of naproxen (dose reduction of naproxen and special monitoring recommended)

Triamterene

Renal failure

Diuretics

Decrease in their blood pressure lowering effect, increased risk of kidney damage (blood pressure and renal function monitoring recommended, and adequate hydration should be ensured)

Potassium-sparing diuretics

Effect may be increased (potassium level monitoring recommended)

Antihypertensives

Decrease in their blood pressure lowering effect (blood pressure monitoring recommended)

ACE inhibitors

Angiotensin II antagonists

Increased risk of nephrotoxicity as a result of inhibition of cyclooxygenase (acute renal failure is possible, especially in older and dehydrated individuals) and increased risk of hyperkalaemia (renal function and potassium level monitoring recommended, and adequate hydration should be ensured)

Methotrexate

Administration of naproxen within 24 hours before or after treatment with methotrexate may lead to an increase in methotrexate blood levels and, therefore, increase the toxicity of the latter (either this combination should be avoided, or blood counts, hepatic and renal function should be monitored very closely)

Ciclosporin

Increased risk of gastrointestinal injuries, nephrotoxicity (avoid combination or use lower dose of naproxen; renal function monitoring recommended)

Oral antidiabetic agents

Blood glucose fluctuations are possible(more frequent blood glucose monitoring recommended)

Antacids

Decreased absorption of naproxen

Paediatric population

Interaction studies have mostly been performed in adults. There is sporadic evidence to suggest that similar interactions are likely in children.

4.6. Fertility, pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformations 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.

From the 20th week of pregnancy onward, naproxen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, 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. Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to naproxen for several days from gestational week 20 onward. Naproxen should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

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

- expose the foetus to:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);

• renal dysfunction (see above);

- expose 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 (see sections 4.3 and 5.3).

Naproxen should not be used post-partum because it may delay involution of the uterus.

Breast-feeding

Small amounts of naproxen pass into breast-milk. Use of Naproxen during breast-feeding should be avoided as a precautionary measure.

Fertility

The use of naproxen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of naproxen should be considered.

4.7. Effects on ability to drive and use machines

Naproxen has minor to moderate influence on the ability to drive and use machines.

If side effects such as visual disturbances, dizziness, fatigue or other CNS disturbances occur, patients should refrain from activities requiring increased alertness – e.g. participating in road traffic or operating machines. Patients should be informed as appropriate.

4.8. Undesirable effects

The most commonly observed adverse events have been gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, may occur – particularly in older patients (see section 4.4). Nausea, vomiting, diarrhoea, bloating, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis and exacerbation of colitis and Crohn's disease have been reported after use of the product. Less frequently, gastritis has been observed.

Oedema, hypertension and cardiac insufficiency have been reported in association with NSAID therapy.

Clinical studies and epidemiological data suggest that the use of some NSAIDs, particularly at high doses and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke).

The reported frequencies of undesirable effects are based on the following categories:

Very common

Common

Uncommon

Rare

Very rare

Not known

(≥ 1/10)

(≥ 1/100 to <1/10)

(≥ 1/1,000 to <1/100)

(≥ 1/10,000 to <1/1,000)

(< 1/10,000)

(cannot be estimated from the available data)

Like other NSAIDs, naproxen may cause the following side effects:

Blood and lymphatic system disorders

Uncommon

Blood count changes, eosinophilia

Very rare

Aplastic or haemolytic anaemia, thrombocytopenia, leukopenia, pancytopenia, agranulocytosis

The following prodromes might occur: fever, sore throat, superficial inflammation of the oral mucosa, flu-like symptoms such as fatigue, nosebleeds and skin bleeding.

Periodic blood counts should be done during long-term use.

Not known

Neutropenia

Immune system disorders

Common

Rash, pruritus

Very rare

Anaphylactic or anaphylactoid systemic reactions – severe and sudden hypotension, acceleration or slowing of the heart rate, unusual tiredness or weakness, anxiety, agitation, unconsciousness, difficulty breathing or swallowing, itching, urticaria with or without angioedema, skin redness, nausea, vomiting, spasmodic abdominal pain or diarrhoea to the point of life-threatening shock

Metabolism and nutrition disorders

Not known

Hyperkalaemia

Psychiatric disorders

Common

Depression, dream abnormalities, insomnia

Nervous system disorders

Common

Headache, dizziness, CNS disorders such as agitation, irritability, sleep disorders, tiredness, perceptual disorders, cognitive dysfunction

Very rare

Seizures, aseptic meningitis in patients with autoimmune disorders (SLE, mixed connective tissue disease), neuritis

Not known

Paraesthesia

Eye disorders

Very rare

Visual disturbances

Not known

Lens swelling and papilloedema, corneal opacity, papillitis

Ear and labyrinth disorders

Common

Tinnitus, hearing impaired, vertigo

Cardiac disorders

Very rare

Hypertension, tachycardia, palpitations, cardiac insufficiency

Vascular disorders

Very rare

Vasculitis

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea

Uncommon

Bronchospasm, asthma attacks (with and without drop in blood pressure), eosinophilic pneumonia

Not known

Pulmonary oedema

Gastrointestinal disorders

Very common

Nausea, vomiting, heartburn, gastric pain, fullness, constipation or diarrhoea and minor blood loss in the gastrointestinal tract which, in exceptional cases, may cause anaemia.

Common

Gastrointestinal ulcers (which may be accompanied by bleeding and perforation)

Uncommon

Haematemesis, melaena or bloody diarrhoea; lower abdominal symptoms (e.g. bleeding colitis or exacerbation of Crohn's disease/ulcerative colitis), stomatitis, oesophageal lesions, flatulence, gastritis

Not known

Pancreatitis

Hepatobiliary disorders

Uncommon

Changes in hepatic function with transaminase elevation

Very rare

Hepatitis (with or without jaundice, may be fulminant in isolated cases), liver damage especially after long-term therapy

Not known

Jaundice

Skin and subcutaneous tissue disorders

Common

Sweating, ecchymoses, purpura

Uncommon

Alopecia (usually reversible), photodermatitis (may include blistering)

Rare

Epidermolysis bullosa-like reactions

Very rare

Hypersensitivity reactions such as skin rash, erythema multiforme, in isolated cases manifesting as severe forms such as Stevens-Johnson syndrome or toxic epidermal necrolysis

Not known

Erythema nodosum, lichen planus, SLE (systemic lupus erythematosus), urticaria, pustular reaction, fixed drug eruption (FDE), Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4)

Musculoskeletal and connective tissue disorders

Uncommon

Myalgia, muscle weakness

Very rare

Worsening of infection-related inflammation (e.g. development of necrotising fasciitis) has been described in temporal relationship with the systemic use of NSAIDs.

Renal and urinary disorders

Common

Peripheral oedema, particularly in patients with hypertension

Uncommon

Acute renal failure, nephrotic syndrome or interstitial nephritis

Very rare

Kidney damage (renal papillary necrosis), especially during long-term therapy, hyperuricaemia

Not known

Haematuria, glomerulonephritis

Reproductive system and breast disorders

Not known

Female infertility

General disorders and administration site conditions

Common

Thirst

Uncommon

Pyrexia (fever and chills), malaise

Not known

Oedema

Investigations

Not known

Serum creatinine increased. Naproxen may interfere with laboratory tests - see section 4.4.

Patients should be apprised that they must discontinue using this medicinal product and seek medical advice immediately if they experience any of the following symptoms:

• Breathlessness

• Large drop in blood pressure

• Clouding of consciousness or severe and/or increasing impairment of overall well-being

• Swelling of the face or throat, difficulty swallowing

• (Itchy) skin rash, redness, vesicles or bleeding of the skin

• Local tender, warm redness and swelling, which may be accompanied by fever

• Severe headache or abdominal pain – especially if onset is sudden

• Haematemesis or coffee grounds-like vomit

• Bloody or black stools

• Heart symptoms (chest pain)

• Severe fatigue with anorexia, with or without yellow colouration of the skin and the sclerae

• Stiff neck with headache

• Visual disturbances or hearing impairment

• Flu-like symptoms, mouth sores, sore throat and nosebleeds.

Paediatric population

The frequency, type and severity of undesirable effects in children and adolescents are similar to those in adults.

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

Symptoms of overdose may include CNS disturbances including headache, dizziness or lightheadedness, and epigastric pain and abdominal discomfort, dyspepsia, nausea, vomiting, transient change in hepatic function, hypoprothrombinaemia, renal dysfunction, metabolic acidosis, apnoea and disorientation. Naproxen can be absorbed rapidly. High and early drug concentrations in the blood should be expected. A few patients have experienced seizures, but it remained unclear whether these were caused by treatment with naproxen. Gastrointestinal bleeding may also occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactic reactions have been described after treatment with non-steroidal anti-inflammatory drugs and may also occur following overdose.

Management of overdose

Patients should be treated symptomatically. There is no specific antidote. Preventive measures to avoid further absorption (e.g. administration of activated charcoal) may be indicated in patients within four hours after ingestion or because of a large overdose. Forced diuresis, alkalinisation of urine, haemodialysis or haemoperfusion are probably unsuitable because of the high protein binding of naproxen.