SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Naproxen 50mg/mL Oral Suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1mL of oral suspension contains 50mg naproxen.

Excipients with known effect

300mg/mL sucrose, 128.6mg/mL sorbitol 70 % solution, 0.5mg/mL methyl-parahydroxybenzoate, 9.2mg/mL sodium.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Oral suspension

White to yellowish-white oral suspension with orange and pineapple flavour

4    CLINICAL PARTICULARS

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 rheumatoid arthritis in children from 2 years of age and older.

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 500750 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 rheumatoid 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 rheumatoid 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.

Skin

Serious skin reactions, some of them with a fatal outcome, 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 such reactions occurred in the majority of cases within the first month of treatment. Naproxen must be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

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

1mL of Naproxen Oral Suspension contains 300mg sucrose (sugar), equivalent to approximately 0.03 carbohydrate exchanges. This should be taken into account in patients with diabetes mellitus.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. May be harmful to the teeth.

Sorbitol

1mL of Naproxen Oral Suspension contains 128.6mg sorbitol 70 % solution. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Sodium

1mL of Naproxen Oral Suspension contains 0.4 mmol (9.2mg) sodium. To be taken into consideration by patients on a controlled sodium diet.

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)
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

Combination of naproxen with	Possible reactions
	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.

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 the 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 oligohydramniosis

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

•    possible prolongation of bleeding time, an anti-platelet 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.

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 breastfeeding 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	(> 1/10)
Common	(> 1/100 to <1/10)
Uncommon	(> 1/1,000 to <1/100)
Rare	(> 1/10,000 to <1/1,000)
Very rare	(< 1/10,000)

Not known (cannot be estimated from the available data)

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

Blood and lymphatic system disorders

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

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.

Hepatobiliary disorders

Changes in hepatic function with transaminase elevation

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

Jaundice

Skin and subcutaneous tissue disorders

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

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

• Not known:    Haematuria, glomerulonephritis

Reproductive system and breast disorders • Not known:    Female infertility

Thirst

Pyrexia (fever and chills), malaise Oedema

Investigations

• Not known:    Serum creatinine increased. Naproxen may interfere with

laboratory tests - see section 4.4.

Other undesirable effects

Methyl-parahydroxybenzoate may cause allergic reactions (possibly delayed).

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, nonsteroids, propionic acid derivatives, naproxen, ATC code: M01AE02.

Mechanism of action

The anti-inflammatory effect of naproxen has even been shown in adrenalectomised animals, suggesting that its mechanism of action is not mediated through the pituitary-adrenal axis. However, the exact mechanism of action is not known.

Pharmacodynamic effects

Naproxen reduces prostaglandin synthesis by inhibiting cyclooxygenase.

This is presumably also the basis of its effects including: analgesia (non-narcotic in nature), anti-inflammatory effect, antipyretic effect, inhibition of platelet aggregation, stabilisation of the lysosomal membrane, bradykinin inhibition and anti-complement effect.

Clinical efficacy and safety

The clinical efficacy and safety of naproxen in the indications listed in section 4.1 has been demonstrated in numerous clinical trials.

Paediatric population

The efficacy and safety of naproxen used in children and adolescents has been demonstrated in numerous studies.

5.2 Pharmacokinetic properties

Absorption

After oral administration, part of a naproxen dose is absorbed from the stomach and then the remainder is absorbed completely from the small intestine, with therapeutic plasma concentrations being reached approximately 2-4 hours post-dose.

Distribution

Patients with renal impairment tend to have lower plasma levels, and those with hepatic impairment tend to have higher plasma levels.

The half-life in healthy individuals and patients with kidney disease is 10 to 18 hours. Older individuals showed no change in half-life, whilst those with hepatic impairment show an increase.

Over 99% of naproxen is reversibly bound to plasma proteins.

Biotransformation and elimination

95% of an administered dose is excreted in the urine both as unchanged drug and as 6-O-desmethylnaproxen either as free drug or in conjugated form.

Linearitv/non-linearitv

The AUC of naproxen shows linear dose proportionality up to a maximum dose of 500mg. Beyond this dose, the proportion of unbound naproxen in plasma increases, leading to an increased renal excretion rate of naproxen.

Pharmacokinetic/pharmacodynamic relationships

The required therapeutically effective plasma concentration ranges from 30-90pg/mL.

Paediatric population

The pharmacokinetic profile of naproxen in children is similar to the profile in adults, but clearance is higher in this age group compared to adults.

5.3 Preclinical safety data

Chronic toxicity studies showed that naproxen exhibited the toxicological profile typical of NSAIDs, i.e. gastrointestinal toxicity and - in high doses - kidney damage.

Naproxen had embryotoxic effects in rats and rabbits, but has not been found to have any teratogenic effects. No adverse effects on male and female fertility were detected in the rat for daily doses up to 30mg/kg, however, higher doses resulted in an inhibition of ovulation in rabbits. Naproxen inhibits prostaglandin synthesis and, therefore, when administered during the last few months of pregnancy, it may delay parturition and have toxic effects on the foetus.

A two-year study in rats produced no evidence of carcinogenic potential. Mutagenicity studies of naproxen gave negative results.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose

Saccharin sodium (E 954)

Sodium cyclamate (E 952)

Sodium chloride

Methyl-parahydroxybenzoate (E 218)

Potassium sorbate (E 202)

Tragacanth (E 413)

Citric acid (E 330)

Sorbitol 70% solution (E 420)

Water

Orange flavour Pineapple flavour

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

24 months.

After first opening: 3 months.

6.4    Special precautions for storage

Store in the original package in order to protect from light.

After first opening: Store in the original package in order to protect from light.

6.5    Nature and contents    of container

Amber glass bottle (type III) with child-resistant screw closure 8mL graduated oral syringe with graduations of 0.1mL Pack of 100mL

6.6    Special precautions for disposal

The bottle is equipped with a child-resistant screw closure. To open, push down and turn the closure. Replace the cap firmly after use.

Cleaning of the oral syringe:

Wash the syringe with water. Disassemble the two parts of the syringe and allow to dry.

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

7    MARKETING AUTHORISATION HOLDER

INFECTOPHARM Arzneimittel und Consilium GmbH

Von-Humboldt-Str. 1

64646 Heppenheim

Germany

Distributed by:

Thornton & Ross Ltd.

Linthwaite Huddersfield HD7 5QH United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 15011/0020

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/06/2016

10    DATE OF REVISION OF THE TEXT

23/06/2016