Data Sheet
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.
Clinical Particulars
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
After assessing the risk/benefit ratio in each individual patient, the lowest effective dose for the shortest possible duration should be used (see Warnings and Precautions).
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 30 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
Naprosyn is contraindicated in patients who have had allergic reactions to prescription as well as to over-the-counter products containing naproxen or naproxen sodium. They are 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.
Naprosyn is contraindicated in patients with active or a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
As with other NSAIDs, Naprosyn is contraindicated in patients with severe heart failure.
Naprosyn is relatively contraindicated in liver dysfunction.
Naprosyn is contraindicated in children under 2 years of age since safety in this age group has not been established.
Warnings and Precautions
The use of Naprosyn with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see Dosage and Administration).
Cardiovascular and cerebrovascular effects
Observational studies have indicated that non-selective NSAIDs may be associated with an increased risk of serious cardiovascular events, including myocardial infarction and stroke which may increase with dose or duration of use. Patients with cardiovascular disease or cardiovascular risk factors may also be at greater risk.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Naprosyn after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). To minimise the potential risk of an adverse cardiovascular event in patients taking an NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration (see Dosage and Administration).
NSAIDs may lead to the onset of new hypertension or worsening of pre-existing hypertension, and patients taking anti-hypertensives with NSAIDs may have an impaired anti-hypertensive response. Caution is advised when prescribing NSAIDs to patients with hypertension. Blood pressure should be monitored closely during initiation of NSAID treatment and at regular intervals thereafter.
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses or long-term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg/d) may be associated with a lower risk, some risk cannot be excluded.
There is no consistent evidence to suggest that concurrent use of aspirin mitigates the possible increased risk of serious cardiovascular thrombotic events associated with NSAID use.
Gastrointestinal effects
All NSAIDs can cause gastrointestinal discomfort and rarely serious, potentially fatal gastrointestinal effects such as ulcers, bleeding and perforation, which may increase with dose or duration of use, but can occur at any time without warning. Upper gastrointestinal ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4 patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious gastrointestinal event at some time during the course of therapy. However, even short- term therapy is not without risk.
Caution is advised in patients with risk factors for gastrointestinal events who may be at greater risk of developing serious gastrointestinal events, e.g. the elderly, those with a history of serious gastrointestinal events, smoking and alcoholism.
NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated. Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment. When gastrointestinal bleeding or ulcerations occur in patients receiving NSAIDs, treatment should be withdrawn immediately. Physicians should warn patients about the signs and symptoms of serious gastrointestinal toxicity.
Studies to date have not identified any subset of patients not at risk of developing peptic ulcer and bleeding However, the elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal. Debilitated patients do not seem to tolerate ulceration or bleeding as well as others. Most of the fatal gastrointestinal events associated with NSAIDs occurred with the elderly and/or debilitated patients.
Caution is advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin. The concurrent use of aspirin and NSAIDs also increase the risk of serious gastrointestinal adverse effects.
Patients with risk factors should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant low dose aspirin or other medicines likely to increase gastrointestinal toxicity.
Precautions relating to elderly patients
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal. In elderly patients, the clearance is reduced. Use of the lower end of the dosage range is recommended (see Dosage and Administration).
Skin reactions
NSAIDs may very rarely cause serious cutaneous adverse events such as exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which can be fatal and occur without warning. These serious adverse events are idiosyncratic and are independent of dose or duration of use. Patients should be advised of the signs and symptoms of serious skin reactions and to consult their doctor at the first appearance of a skin rash or any other sign of hypersensitivity.
Anaphylactic 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.
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 Naprosyn.
As with other NSAIDs, Naprosyn 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 as renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of Naprosyn 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 Naprosyn is usually followed by recovery to the pretreatment state. Naprosyn 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 30 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.
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.
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 Naprosyn is 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 Naprosyn concurrently.
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 Naprosyn administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilloedema, have been reported in users of NSAIDs including Naprosyn, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with Naprosyn should have an ophthalmological examination.
Sodium/fluid retention in cardiovascular conditions and peripheral oedema
Naprosyn Suspension contains sodium chloride. This should be considered in patients whose overall intake of sodium should be markedly restricted.
Although sodium retention has not been reported in metabolic studies with Naprosyn, patients with compromised cardiac function may be at greater risk when taking Naprosyn, and caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Peripheral oedema has been observed in some patients taking Naprosyn or other NSAIDs.
Precautions related to fertility
The use of Naprosyn, 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 Naprosyn should be considered.
Combination with other NSAIDs
The combination of Naprosyn and other NSAIDs is not recommended, because of the cumulative risks of inducing serious NSAID-related adverse events.
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.
Interactions with Other Medicinal 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 Naprosyn and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.
Although no significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants, NSAIDs may enhance the effects of anticoagulants, such as warfarin. Naprosyn decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
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.
Naprosyn can reduce the anti-hypertensive effect of beta blockers.
As with other non-steroidal anti-inflammatory medicines, Naprosyn 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).
There is an increased risk of gastrointestinal bleeding (see Warnings and Precautions) when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.
Use in Special Populations
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, Naprosyn should not be used during pregnancy unless clearly needed.
Labour and delivery
Naprosyn are not recommended in labour and delivery because, through its prostaglandin synthesis inhibitory effect, Naprosyn 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.
Undesirable Effects
Post-Marketing
The following are the adverse events have been reported with NSAIDs and with naproxen:
Gastrointestinal: peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal particularly in the elderly (see Warnings and Precautions); heartburn, nausea, oesophagitis, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, non-peptic gastrointestinal ulceration, melaena, haematemesis,stomatitis, ulcerative stomatitis, exacerbation of ulcerative colitis and Crohn's disease (see Warnings and Precautions), pancreatitis, gastritis
Infections: aseptic meningitis
Blood and lymphatic system disorders: agranulocytosis, aplastic anaemia, eosinophilia, haemolytic anaemia, leucopoenia, thrombocytopenia
Immune system disorders: anaphylactoid reactions
Metabolic and nutrition disorders: hyperkalaemia
Psychiatric disorders: depression, dream abnormalities, insomnia
Nervous system disorders: dizziness, drowsiness, headache, light-headedness, retrobulbar optic neuritis, convulsions, cognitive dysfunction, inability to concentrate
Eye disorders: visual disturbances, corneal opacity, papillitis, papilloedema
Ear and labyrinth disorders: hearing impairment, hearing disturbances, tinnitus, vertigo
Cardiac disorders: palpitations, cardiac failure has been reported in association with NSAIDs treatment, congestive heart failure
Vascular disorders: hypertension, vasculitis
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggests that the use of naproxen (1000 mg/d) may be associated with a lower risk, some risk cannot be excluded.
Respiratory, thoracic and mediastinal disorders: dyspnoea, pulmonary oedema, asthma, eosinophilic pneumonitis
Hepatobiliary disorders: hepatitis (some cases of hepatitis have been fatal), jaundice
Skin and subcutaneous tissue disorders: ecchymoses, itching (pruritus), purpura, skin eruptions, sweating, alopecia, epidermal necrolysis, very rarely toxic epidermal necrolysis, erythema multiforme, bullous reactions, including Stevens-Johnson syndrome, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, skin rashes, systemic lupus erythematosus, urticaria, photosensitivity reactions including rare cases resembling porphyria cutanea tarda ("pseudoporphyria"), or epidermolysis bullosa, and angioneurotic oedema
If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.
Musculoskeletal and connective tissue disorders: myalgia, muscle weakness
Renal and urinary disorders: haematuria, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis
Reproductive system and breast disorders: female infertility
General disorders and administration site conditions: oedema, thirst, pyrexia (chills and fever), malaise
Investigations: abnormal liver function tests, raised serum creatinine
Overdosage
Symptoms
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.
Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.
Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Treatment
Patients should be managed by symptomatic and supportive care following NSAIDs overdose. There are no specific antidotes. Prevention of further absorption (e.g. activated charcoal) may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinisation of urine, haemodialysis, or haemoperfusion may not be useful due to high 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 <10 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.
Impairment of Fertility
Naprosyn did not affect the fertility of rats when administered orally at doses of 30 mg/kg/day to males and 20 mg/kg/day to females.
Teratogenicity
Naprosyn was not teratogenic when administered orally at doses of 20 mg/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.
*Naprosyn EC 250mg and 500mg tablets: Protect from light. Store at or below 30°C.
Naprosyn SR 750mg and 1000mg Tablets: Protect from light, store at or below 30°C.
*Naprosyn 25mg/mL Suspension: Protect from light. Store at or below 25°C.
Instructions for use, handling and disposal
Naprosyn Suspension: shake gently before use.
Medicine Classification
Prescription medicine
Packs
Naprosyn SR 750mg tablets 90's
Naprosyn SR 1000mg tablets 90's
Name and Address
Roche Products (New Zealand) Ltd
P O Box 12-492
Penrose
AUCKLAND
Telephone: (09) 633 0700
Telefax: (09) 633 0722
Toll Free: 0800 656 464
Date of Preparation
12 November 2007
Reference: International Core Data Sheet V4 , 15 February 2007
*Please note, the following presentations are not marketed:
Naprosyn 250mg and 500mg tablets.
Naprosyn EC 250mg and 500mg tablets.
Naprosyn 25mg/mL suspension.