Naprosyn^®

Naproxen 250mg and 500mg tablets; 250mg and 500mg enteric coated (EC) tablets; 750mg and 1000mg sustained release (SR) tablets; 25mg/mL suspension.

Non-steroidal anti-inflammatory agent.

Pharmaceutical Form

Naprosyn tablet

250mg: round, yellow, uncoated tablets, embossed `NPR LE 250' on one face and a breakline on the other.

500mg: oblong, yellow tablets engraved `NPR LE 500' on one face and a break-score on the other.

Naprosyn EC (enteric coated) tablet

250mg: a flat, white, round tablet, 9.5mm in diameter, inscribed NPR EC 250 on one side. The 250 is imprinted below NPR EC.

500mg: a capsule shaped, white tablet, 16mm by 7mm, inscribed NPR EC 500 on one side. The 500 is imprinted below NPR EC.

Naprosyn SR (sustained release) tablet

750mg: a capsule shaped, peach coloured, sustained release tablet, 8.9mm by 17.8mm, NPR SR-750 on one side.

1000mg: a capsule shaped, peach coloured, sustained release tablet 9.4 mm by 20.3 mm, NPR SR-1000 on one side.

Naprosyn suspension

25mg/mL: the suspension is white to off-white with uniformly distributed particles and a pineapple-orange odour.

Qualitative and Quantitative Composition

Active ingredient

Naproxen

Naprosyn Tablets: tablets containing naproxen 250 mg, 500 mg.

Naprosyn EC Tablets: enteric-coated tablets containing naproxen 250 mg, 500 mg.

Naprosyn SR Tablets: sustained release tablets containing naproxen 750mg, 1000mg.

Naprosyn Suspension: suspension containing naproxen 25 mg/mL.

Excipients

Naprosyn 250mg and 500mg Tablets

Povidone (K-90), croscarmellose sodium (Type A), magnesium stearate, iron oxide, purified water.

Naprosyn EC 250mg and 500mg Tablets

Core: povidone (K-90), croscarmellose sodium (Type A), magnesium stearate, purified water.

Coating: methacrylic acid copolymer (Type C), talc, sodium hydroxide, triethyl citrate, purified water.

Printing ink: black printing ink (Opacode S-1-8106 and Opacode S-1-8106M), talc.

Naprosyn SR 750mg and 1000mg Tablets

Hydroxypropyl methyl cellulose, magnesium stearate, FDC yellow 6, purified water.

Naprosyn 25mg/mL Suspension

Sucrose, sorbitol, sodium chloride, aluminium magnesium silicate, fumaric acid, methyl hydroxybenzoate, imitation orange flavour, imitation pineapple flavour, purified water.

Therapeutic Indications

Naprosyn tablets and suspension are indicated for its anti-inflammatory and analgesic action in the treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis), ankylosing spondylitis, juvenile rheumatoid arthritis, acute gout, acute musculoskeletal disorders, post-operative pain and dysmenorrhoea.

Naprosyn EC tablets are indicated for its anti-inflammatory and analgesic action in the treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis) and ankylosing spondylitis.

Naprosyn SR tablets are indicated for its anti-inflammatory and analgesic action in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other musculoskeletal disorders.

Dosage and Method of Administration

General

Although naproxen and naproxen sodium-containing products all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen.

The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events.

A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients. Naprosyn is not recommended in patients with baseline creatinine clearance less than 20 mL/minute because accumulation of naproxen metabolites has been seen in such patients.

During long-term administration the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. In patients who tolerate lower doses well, the dose may be increased to 1000 mg per day when a higher level of anti-inflammatory/analgesic activity is required. When treating patients with naproxen 1000 mg/day, the physician should observe sufficient increased clinical benefit to offset the potential increased risk (see Precautions).

The morning and evening doses do not have to be equal in size and administration of the medicine more frequently than twice daily does not generally make a difference in response.

Standard dosage

Recommended formulations

Because the sodium salt of naproxen is more rapidly absorbed, naproxen sodium is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Naprosyn Suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the child's weight. Naprosyn EC is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products.

Naprosyn may be given orally either in fasting state or with meals and/or antacids. To maintain the integrity of the enteric coating, the Naprosyn EC tablet should not be broken, crushed or chewed during ingestion. Naprosyn Suspension should be shaken gently before use.

Caution is required with dosage in the elderly and also in patients with renal impairment.

Naprosyn and Naprosyn SR (sustained release) tablets

Adults

For rheumatoid arthritis, osteoarthritis and ankylosing spondylitis

Initial therapy

The usual dose is 500-1000 mg per day taken in two doses at 12 hour intervals. The tablets should be swallowed whole with liquid preferably after meals. Where 1000 mg per day is needed, the suggested regimen is one Naprosyn 500 mg tablet twice daily.

Maintenance treatment

The maintenance dose is usually 500 mg per day taken in two doses at 12 hour intervals, i.e. 250 mg on awakening and 250 mg before retiring. The tablets should be swallowed whole with liquid preferably after meals. Dosage adjustments within the range of 500-1000 mg per day, maintaining 12 hour interval administration, may be employed. The size of the morning and evening doses should be adjusted on the basis of predominant symptoms, i.e. night time pain or morning stiffness.

Alternatively, patients stabilised on a daily maintenance dose of 500 mg, 750 mg or 1000 mg may administer their daily requirements as a single dose as naproxen has been shown to be effective when administered as a single daily dose. For convenience, patients stabilised on a daily maintenance dose of 750 mg or 1000 mg naproxen may administer their daily requirements by using the corresponding Naprosyn SR tablet at night with food or milk. The Naprosyn SR tablets must not be chewed or broken.

The total daily dose of naproxen should not exceed 1000 mg maintaining 12 hour interval administration.

For acute gout

750 mg should be given initially, followed in 8 hours with 500 mg, and thereafter 250 mg at 8 hour intervals until the attack has passed.

For dysmenorrhoea

500 mg should be given initially, followed by 250 mg at 6-8 hour intervals for up to 5 days, if necessary.

For adult usage in other indications (analgesia and acute muscular skeletal disorders)

500 mg should be given initially, followed by 250 mg at 6-8 hour intervals, if necessary.

Children

For juvenile rheumatoid arthritis

The usual dose for children over 5 years is 10 mg/kg/day given as two divided doses at 12 hour intervals. Therapy in children under 5 years of age is not recommended.

Naprosyn EC (enteric coated) tablets

Adults

For rheumatoid arthritis, osteoarthritis and ankylosing spondylitis

Initial therapy

The usual dose is 500mg to 1000mg per day taken in two doses at 12 hour intervals. The tablets should be swallowed whole with liquid, preferably after meals.

Maintenance treatment

The maintenance dose is usually 500mg per day taken in two doses at 12-hour intervals. Dosage adjustments within the range of 500 to 1000mg per day, maintaining 12-hour interval administration, may be employed. The size of the morning and evening doses should be adjusted on the basis of predominant symptoms, i.e. night-time pain or morning stiffness.

The total daily dose of naproxen should not exceed 1000mg.

Children

The safety of Naprosyn EC for paediatric use has not been established.

Naprosyn Suspension

Shake the suspension gently before use.

Adults

Dosage is the same as that for Naprosyn tablets and Naprosyn SR tablets. The adult dose of 500-1000mg tablets per day is equivalent to 10-20 mL twice daily of Naprosyn Suspension.

Children

The usual dose for children over 5 years is 10 mg/kg/day given as two divided doses at 12 hour intervals. Therapy in children under 5 years of age is not recommended.

Contraindications

All naproxen products are contraindicated in patients who have had allergic reactions to prescription as well as to over-the-counter products containing naproxen or naproxen sodium. It is also contraindicated in patients in whom aspirin or other nonsteroidal anti-inflammatory/ analgesics induce the syndrome of asthma, rhinitis and nasal polyps. Both types of reactions have the potential of being fatal. Severe anaphylactic-like reactions to naproxen have been reported in such patients.

All products containing naproxen or naproxen sodium are CONTRAINDICATED in patients with active peptic ulceration or active gastrointestinal bleeding, patients with asthma and in patients with haemorrhagic diathesis.

Naprosyn is relatively contraindicated in liver dysfunction.

Products containing naproxen or naproxen sodium are contraindicated in children under 2 years of age since safety in this age group has not been established.

Special Warnings and Special Precautions for Use

Gastrointestinal ulceration, bleeding and perforation

Gastrointestinal mucosal injury may occur. Serious gastrointestinal toxicity, such as gastrointestinal irritation, bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated with NSAIDs including naproxen therapy. Studies to date have not identified any subset of patients not at risk of developing peptic ulcer and bleeding. Postmarketing experience with naproxen and with other NSAIDs suggests that there may be a greater risk of gastrointestinal ulceration, bleeding and perforation in elderly and debilitated patients, who seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with non-steroidal anti-inflammatory medicines occurred in this patient population.

In patients with a history of gastrointestinal disease, Naprosyn should be given under close supervision. Open studies in patients with rheumatoid arthritis who had upper gastrointestinal dysfunction and/or were intolerant of other commonly used NSAIDs indicated that naproxen is generally well tolerated.

As with other nonsteroidal anti-inflammatory medicines, the incidence and severity of gastrointestinal complications may increase with increasing dose and duration of treatment with Naprosyn.

In clinical trials, the number of patients receiving Naprosyn EC who developed severe gastrointestinal symptoms was decreased as compared to patients who received Naprosyn. The number of patients who withdrew prematurely for gastrointestinal symptoms was reduced among those who received Naprosyn EC.

Renal effects

There have been reports of impaired renal function, renal failure, acute interstitial nephritis, haematuria, proteinuria, renal papillary necrosis and occasionally nephrotic syndrome associated with naproxen-containing products.

As with other NSAIDs, naproxen-containing products should be used with caution in patients with impaired renal function or a history of kidney disease because naproxen is an inhibitor of prostaglandin synthesis. Caution should be observed in patients with conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of naproxen-containing products or other NSAIDs may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal decompensation or failure. Patients at greatest risk of this reaction are those with impaired renal function, hypovolaemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and the elderly. Discontinuation of naproxen-containing products is usually followed by recovery to the pretreatment state. Naproxen-containing products should be used with great caution in such patients and the monitoring of serum creatinine and/or creatinine clearance is advised. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.

Naproxen-containing products are not recommended in patients with baseline creatinine clearance less than 20 mL/min because accumulation of naproxen metabolites has been seen in such patients.

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

Haematological

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

Patients who have coagulation disorders or are receiving therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered. Patients at high risk of bleeding and those on full anticoagulation therapy (e.g. dicoumarol derivatives) may be at increased risk of bleeding if given naproxen-containing products concurrently.

Anaphylactic (anaphylactoid) reactions

Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur, both in patients with and without a history of hypersensitivity or exposure to aspirin, other non-steroidal anti-inflammatory medicines or naproxen-containing products. They may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma), rhinitis and 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 or allergic disease or aspirin sensitivity.

Hepatic effects

As with other non-steroidal anti-inflammatory medicines, elevations of one or more liver function tests may occur. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Severe hepatic reactions, including jaundice and hepatitis (some cases of hepatitis have been fatal) have been reported with this medicine as with other non-steroidal anti-inflammatory medicines. Cross reactivity has been reported.

Antipyretic effects

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

Steroids

If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Ocular effects

Studies have not shown changes in the eye attributable to naproxen administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including naproxen, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with naproxen-containing products should have an ophthalmological examination.

Sodium

Naprosyn Suspension contains sodium chloride. This should be considered in patients whose overall intake of sodium should be markedly restricted.

Oedema

Peripheral oedema has been observed in some patients. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at greater risk when taking naproxen.

Precautions related to elderly patients

Elderly patients may be at a greater risk of experiencing undesirable effects than younger patients. In elderly patients the clearance is reduced. Use of the lower end of the dosage range is recommended (see Dosage and Method of Administration).

Precautions related to fertility

The use of naproxen, as with any medicine known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility withdrawal of naproxen should be considered.

Combination with other NSAIDs

The combination of naproxen-containing products and other NSAIDs is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.

Interactions with Other Medical Products and other Forms of Interaction

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

Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound medicines such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants, however caution is advised since interactions have been seen with other nonsteroidal agents of this class, the free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function.

Caution is advised when probenecid is administered concurrently, since increases in naproxen plasma concentrations and increased half-life of naproxen have been reported with this combination.

Caution is advised when methotrexate is administered concurrently, since naproxen and other prostaglandin synthesis-inhibiting medicines have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity.

Naproxen can reduce the anti-hypertensive effect of beta blockers.

As with other non-steroidal anti-inflammatory medicines, naproxen may inhibit the natriuretic effect of frusemide.

Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has been reported.

It is suggested that Naprosyn therapy should be temporarily discontinued 48 hours before adrenal function tests are performed, because naproxen may artefactually interfere with some tests for 17-ketogenic steroids. Similarly, Naprosyn therapy may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).

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

Pregnancy and Lactation

Pregnancy

As with other medicines of this type, naproxen produces delay in parturition in animals and also affects the human foetal cardiovascular system (closure of ductus arteriosus). Therefore, naproxen should not be used during pregnancy unless clearly needed.

Labour and delivery

Naproxen-containing products are not recommended in labour and delivery because, through its prostaglandin synthesis inhibitory effect, naproxen may adversely affect foetal circulation and inhibit uterine contractions, thus increasing the risk of uterine haemorrhage.

Nursing mothers

The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in plasma. Because of the possible adverse effects of prostaglandin-inhibiting medicines on neonates, use in nursing mothers is not recommended.

Effects on Ability to Drive and Use Machines

Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of Naprosyn. If patients experience these or similar undesirable effects, they should exercise caution in carrying out activities that require alertness.

Undesirable Effects

The following are the adverse events observed most frequently in association with naproxen and naproxen sodium:

• Gastrointestinal: abdominal pain, constipation, diarrhoea, dyspepsia, heartburn, nausea, stomatitis
• Central nervous system: dizziness, drowsiness, headache, light-headedness, vertigo
• Dermatologic: ecchymoses, itching (pruritus), purpura, skin eruptions, sweating
• Special senses: hearing disturbances, tinnitus, visual disturbances
• Cardiovascular: dyspnoea, oedema, palpitations
• General: thirst

The following adverse events have also been reported:

• Gastrointestinal: abnormal liver function tests, colitis, oesophagitis, gastrointestinal bleeding and/or perforation, haematemesis, hepatitis (some cases of hepatitis have been fatal), jaundice, melena, nonpeptic gastrointestinal ulceration, pancreatitis, peptic ulceration, ulcerative stomatitis, vomiting
• Renal: haematuria, hyperkalaemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine
• Haematological: agranulocytosis, aplastic anaemia, eosinophilia, haemolytic anaemia, leukopenia, thrombocytopenia
• Central nervous system: aseptic meningitis, cognitive dysfunction, convulsions, depression, dream abnormalities, inability to concentrate, insomnia, malaise, myalgia, muscle weakness
• Dermatologic: alopecia, epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, skin rashes, SLE (systemic lupus erythematosus), Stevens-Johnson syndrome, urticaria, photosensitivity reactions including rare cases resembling porphyria cutanea tarda ("pseudoporphyria") or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored
• Special senses: hearing impairment
• Cardiovascular: congestive heart failure, hypertension, pulmonary oedema, vasculitis
• Reproductive, female: infertility
• Respiratory: asthma, eosinophilic pneumonitis
• General: anaphylactoid reactions, angioneurotic oedema, pyrexia (chills and fever)
• Special senses: corneal opacity, papillitis, retrobulbar optic neuritis and papilloedema

Overdosage

Significant naproxen overdosage may be characterised by dizziness, drowsiness, epigastric pain, abdominal discomfort, indigestion, nausea, transient alterations in liver function, hypoprothrombinaemia, renal dysfunction, metabolic acidosis, apnoea, disorientation or vomiting. A few patients have experienced convulsions, but it is not clear whether or not these were naproxen related.

Should a patient ingest a large amount of naproxen-containing products, accidentally or purposefully, the stomach should be emptied and the usual supportive measures employed. Animal studies indicate that the prompt administration of 50-100g of activated charcoal as an aqueous slurry over 15 minutes within 2 hours of the overdose would tend to reduce markedly the absorption of the medicine. Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding.

Pharmacological Properties and Effects

Pharmacodynamic Properties

Naprosyn (naproxen) is a nonsteroidal anti-inflammatory (NSAID) with analgesic, anti-inflammatory and antipyretic properties. The onset of pain relief is more rapid with naproxen sodium than with Naprosyn, therefore naproxen sodium is recommended for the management of acute painful conditions.

Naproxen is a propionic acid derivative related to the arylacetic acid class of medicines. The chemical name of naproxen is (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid. It is an odourless, white to off-white crystalline substance. It is lipid soluble, practically insoluble in water at low pH and freely soluble in water at high pH.

Mechanism of action

Naproxen has been shown to have striking anti-inflammatory properties when tested in human clinical studies and classical animal test systems. In addition, it has marked analgesic and antipyretic actions. It exhibits its anti-inflammatory effects even in adrenalectomised animals, indicating that its action is not mediated through the pituitary axis. It inhibits synthesis of prostaglandins. As with other similar agents, however, the exact mechanism of its anti-inflammatory action is not known.

Pharmacokinetic Properties

Absorption

Naproxen and naproxen sodium are rapidly and completely absorbed from the gastrointestinal tract after oral administration. Naproxen sodium is more rapidly absorbed than naproxen. Concomitant administration of food can delay the absorption of naproxen and naproxen sodium, but does not affect its extent.

Naprosyn tablets: After administration of Naprosyn tablets, peak plasma levels are attained in 2 to 4 hours depending on food intake.

Naprosyn EC tablets: Enteric-coated naproxen dissolves primarily in the small bowel rather than the stomach, so the absorption is delayed until the stomach is emptied. When multiple doses of naproxen are administered in the EC form, the peak plasma levels, elimination half-life and the area under the plasma concentration-time curve at steady state are comparable to the non-EC form of naproxen. Naprosyn EC given as a single dose with food resulted in peak plasma levels in about 12 hours (range 4 - 24 hours). In fasted subjects, peak plasma levels are attained in about 4 hours following the first dose.

Naprosyn SR tablets: When naproxen is administered in the sustained release form (Naprosyn SR), the mean areas under the plasma concentration-time curves are equivalent for the SR and non-SR formulations. The peak plasma levels are delayed and the maximum plasma concentrations reduced compared with the non-SR formulations of naproxen. The minimum plasma concentrations are equivalent for Naprosyn SR given once a day and corresponding non-SR dosage given twice a day (i.e. 1000 mg or 750 mg Naprosyn SR and 500 mg or 250 mg Naprosyn tablets). The peak to trough plasma concentration ratio of 2.6 observed with non-SR formulations is reduced to 1.8 with Naprosyn SR.

Naprosyn suspension: Peak plasma levels of naproxen given as Naprosyn Suspension are attained in 1 - 4 hours.

Distribution

Naproxen has a volume of distribution of 0.16 l/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. However, the concentration of unbound naproxen continues to increase proportionally to dose.

Steady-state plasma levels of naproxen are reached after 3 - 4 days.

Naproxen enters synovial fluid, crosses the placenta and has been found in the milk of lactating mothers at a concentration approximately 1% of that found in plasma.

Metabolism

Naproxen is extensively metabolised in the liver to 6-0-desmethyl naproxen.

Elimination

Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%), or their conjugates (66 - 92%). The rate of excretion of metabolites and conjugates has been found to coincide closely with the rate of naproxen disappearance from the plasma. Small amounts, 3% or less, are excreted in the faeces.

The clearance of naproxen is approximately 0.13 mL/min/kg. The elimination half-life of naproxen is approximately 14 hours and is independent of the chemical form or the formulation.

Pharmacokinetics in special clinical situations

Renal impairment

Given that naproxen and its metabolites are primarily excreted by the kidney, the potential exists for accumulation in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. In patients who are severely renally impaired (creatinine clearance <20 mL/min), there is higher clearance of naproxen than estimated from the degree of renal impairment alone.

Children

The pharmacokinetic profile of naproxen in children aged 5 - 16 years is similar to that in adults although the clearance is generally higher in children than in adults. Pharmacokinetic studies of naproxen were not performed in children less than 5 years of age.

Preclinical Safety

Carcinogenicity

Naprosyn was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24 mg/kg/day. Naprosyn was not carcinogenic in rats.

Mutagenicity

Mutagenicity was not seen in Salmonella typhimurium (5 cell lines), Sachharomyces cerevisisae (1 cell line), and mouse lymphoma tests.

Fertility

Naprosyn did not affect the fertility of rats when administered orally at doses of 30mg/kg/day to males and 20mg/kg/day to females.

Teratogenicity

Naprosyn was not teratogenic when administered orally at doses of 20mg/kg/day during organogenesis to rats and rabbits.

Perinatal/postnatal reproduction

Oral administration of Naprosyn to pregnant rats at doses of 2, 10 and 20 mg/kg/day during the third trimester of pregnancy resulted in difficult labour. These are known effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indomethacin.

Pharmaceutical Particulars

Incompatibilities

None known.

Stability

This medicine must not be used after the expiry date shown on the pack.

Special remarks

Special Precaution for Storage

Naprosyn 250mg and 500mg Tablets: Protect from light, store at or below 30°C (86°F).

Naprosyn EC 250mg and 500mg tablets: Protect from light. Store at or below 30°C (86°F).

Naprosyn SR 750mg and 1000mg Tablets: Protect from light, store at or below 30°C (86°F).

Naprosyn 25mg/mL Suspension: Protect from light. Store at or below 25°C (77°F).

Instructions for use, handling and disposal

Naprosyn Suspension: shake gently before use.

Packs

   Inhouse Pharmacy (UK)