Data Sheet
APO-NAPROXEN SR
Naproxen 750mg Sustained Release Tablets 750mg
Presentation
APO-NAPROXEN SR 750mg tablets are peach coloured, capsule shaped, biconvex tablets, 8.7mm x 17.5mm, identified APO-750 on one side. Each tablet contains 750mg naproxen and typically weighs 780mg.
Uses
Actions
Naproxen, a propionic acid derivative, is a non-steroidal anti-inflammatory drug (NSAID) which exhibits anti-inflammatory, analgesic and antipyretic activity. The exact mode of action is not known but many of its effects are associated with a decrease in prostaglandin synthesis following inhibition of the cyclo-oxygenase enzyme. Prostaglandins play a major role in the mediation of pain, fever and inflammation. Additional inhibitory effects of naproxen on the formation and migration of other mediators of inflammation have also been proposed.
Prostaglandins appear to sensitise pain receptors to mechanical stimulation and to other chemical mediators (e.g. bradykinin, histamine). In addition, prostaglandins E2 and F2 proportionally increase the amplitude and frequency of uterine contractions and are thought to be responsible for primary dysmenorrhoea.
As well as providing relief from pain and any underlying inflammation in various conditions (see Indications), naproxen can also be used for symptomatic treatment of stiffness, swelling and tenderness. Furthermore, it can improve grip strength and mobility in people with rheumatic disease.
Pharmacokinetics
Naproxen is almost completely (97%) absorbed from the gastro-intestinal tract after oral administration. Peak plasma levels are attained within 2 to 4 hours. The presence of food delays the rate but not the extent of absorption. When naproxen is administered in the sustained release form the peak plasma levels are delayed and the maximum plasma concentrations reduced compared with standard release formulations of naproxen. The minimum plasma concentrations at steady state are equivalent between naproxen sustained release given once a day and the corresponding standard dosage given twice daily.
The apparent volume of distribution of naproxen averages about 8.3L in healthy adults and about 11.9 L in patients with severe renal failure. Naproxen is 99% bound to plasma proteins and when binding sites become saturated, urinary clearance increases. Plasma naproxen concentrations tend to plateau when dosage exceeds 500mg twice daily. The elimination half-life of naproxen is 13 hours and steady-state plasma concentrations are achieved after 2 to 3 days. Naproxen diffuses into synovial fluid, crosses the placenta and is distributed into breast milk.
Approximately 30% of the dose of naproxen is metabolised in the liver to inactive metabolites, and 95% of the dose is excreted in urine as unchanged naproxen (<1%), 6-0-desmethylnaproxen (1%), and their conjugates (66-92%). Less than 5% of a dose has been recovered from the faeces.
Relief from mild to moderate paid is evident within 1 hour and the duration of effect is about 7 hours. Analgesia is usually maximal at 2 hours, whereas relief from the pain and inflammation of an acute attack of gout occurs within 24 to 48 hours.
Indications
APO-NAPROXEN SR are indicated for their anti-inflammatory and analgesic action in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other musculoskeletal disorders.
Dosage and Administration
After assessing the risk/benefit ratio in each individual patient, the lowest effective dose for the shortest duration should be used.
One tablet once daily. APO-NAPROXEN SR tablets should be taken with food or milk. They must be swallowed whole.
Caution is required with dosage in the elderly and in patients with renal impairment.
APO-NAPROXEN SR is not intended for patients requiring short-term treatment for acute conditions.
APO-NAPROXEN SR is not suitable for children because of its dosage strength.
Contraindications
Hypersensitivity to naproxen or naproxen sodium.
History of or active peptic or gastrointestinal ulceration or chronic dyspepsia.
Active gastrointestinal bleeding.
History of aspirin or other NSAID induced allergic manifestations e.g. asthma, rhinitis, urticaria.
Warnings and Precautions
Cardiovascular Thrombotic Events
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. 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).
There is no consistent evidence that the concurrent use of aspirin mitigates
the possible increased risk of serious cardiovascular thrombotic events
associated with NSAID use.
Hypertension
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.
Heart failure
Fluid retention and oedema have been observed in some patients taking NSAIDs; therefore caution is advised in patients with fluid retention or heart failure.
Gastrointestinal Events
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 GI ulcers, gross bleeding or perforation
caused by NSAIDs occur approximately 1% of patients treated for 3-6 months and
in about 2-4% patents treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI 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. When gastrointestinal bleeding or ulcerations occur in
patients receiving NSAIDs, the drug should be withdrawn immediately. Doctors
should warn patients about the signs and symptoms of serious gastrointestinal
toxicity.
The concurrent use of aspirin and NSAIDs also increases the risk of serious
gastrointestinal adverse events.
Severe Skin Reactions
NSAIDs may 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 sign of hypersensitivity.
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. Naproxen containing products should be used with care 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 flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of naproxen containing products may cause a dose dependent reduction in renal prostaglandin formation and may precipitate overt renal decompensation or failure. Patients at greatest risk are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and the elderly. Discontinuation of naproxen containing products usually results in recovery to the pretreatment state. Monitoring of serum creatinine and/or creatinine clearance is recommended in at risk patients. A reduction in the daily dosage should be considered to prevent the possibility of excessive accumulation of naproxen metabolites in these patients. Naproxen containing products are not recommended for patients with a baseline creatinine clearance of less than 20ml/min because accumulation of naproxen metabolites has been seen in such patients. Haemodialysis does not decrease the plasma concentration of naproxen due to the high level of protein binding.
Haematological
Naproxen decreases platelet aggregation and prolongs bleeding time. Patients who have coagulation disorders or are receiving therapy that interferes with haemostatis should be carefully monitored if administered naproxen containing products. Patients at high risk of bleeding or receiving full anticoagulation therapy may be at increased risk if given naproxen containing products concomitantly.
Anaphylactic reactions
Anaphylactic reactions may occur in patients with or without a history of hypersensitivity or exposure to aspirin, other NSAIDs or naproxen containing products. They may also occur in individuals with a history of angioedema, bronchospastic reactivity e.g. asthma, rhinitis, and nasal polyps. Bronchospasm may be precipitated in patients suffering from or with a history of asthma, allergic disease or aspirin sensitivity.
Hepatic effects
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 have been reported. Cross reactivity has been reported.
Antipyretic effects
The antipyretic and anti-inflammatory effects of naproxen may mask the usual signs or symptoms of infection.
Steroids
If steroid dosage is reduced or eliminated during therapy the steroid dosage should be reduced slowly and the patients closely monitored for evidence of adverse effects including adrenal insufficiency and exacerbation of arthritis symptoms.
Ocular effects
Adverse ophthalmological effects have been observed with NSAIDs. Patients who develop visual disturbances during treatment with APO-NAPROXEN SR should have an opthamological examination.
Oedema
Peripheral oedema has been observed in some patients. It is possible that patients with questionable or compromised cardiac function may be at greater risk.
Elderly patients
Elderly patients may be at greater risk of adverse effects than younger patients.
Driving and operating machinery
Some patients may experience drowsiness, dizziness, vertigo, vertigo, insomnia or depression. They should exercise caution in carrying out activities that require alertness.
Use in Pregnancy and Lactation
Category C.
Naproxen inhibits prostaglandin synthesis and when given in the latter part of pregnancy may cause closure of the foetal ductus arteriosus, prolong labour and delay birth. Treatment with naproxen during pregnancy should only be given if the potential benefit justifies the potential risk.
Naproxen has been detected in breastmilk. Because of the possible adverse effects on the neonate use of naproxen in nursing mothers is not recommended.
Adverse Effects
Adverse effects for APO-NAPROXEN SR are similar to those reported for standard naproxen. The most commonly reported side-effects relate to the gastrointestinal tract.
Gastrointestinal
More common (3 to 9%): Constipation, heartburn, abdominal pain and nausea.
Less common (1 to 3 %): Dyspepsia, diarrhoea, stomatitis.
Less frequent (<1%): Abnormal liver function tests, gastrointestinal bleeding, haematemesis, jaundice, melaena, peptic ulceration with bleeding and/or perforation, vomiting, nonpeptic gastrointestinal ulcerations, ulcerative stomatitis, colitis, fatal hepatitis.
Central Nervous System
More common (3 to 9%): Headache, dizziness, drowsiness.
Less common (1 to 3 %): Lightheadedness, vertigo.
Less frequent (<1%): Depression, dream abnormalities, inability to concentrate, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis.
Causal relationship unknown: Cognitive dysfunction, convulsions, paraesthesiae.
Dermatological
More common (3 to 9%): Itching (pruritis), skin eruptions, ecchymoses.
Less common (1 to 3 %): Sweating, purpura.
Less frequent (<1%): Porphyria cutanea tarda, alopecia, skin rashes, epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, photosensitivity reactions including rare cases in which skin resembled porphyria cutanea tarda or epidermolysis bullosa.
Causal relationship unknown: Urticaria.
Special senses
More common (3 to 9%): Tinnitus.
Less common (1 to 3 %): Hearing disturbances, visual disturbances.
Less frequent (<1%): Hearing impairment.
Cardiovascular
More common (3 to 9%): Oedema, dyspnoea.
Less common (1 to 3 %): Palpitations.
Less frequent (<1%): Congestive heart failure, vasculitis.
Renal
Less frequent (<1%): Glomerular nephritis, haematuria, interstital nephritis, nephrotic syndrome, renal disease, renal papillary necrosis, renal failure.
Haematological
Less frequent (<1%): Eosinophilia, granulocytopenia, leucopenia, thrombocytopenia.
Causal relationship unknown: Agranulocytosis, aplastic anaemia, haemolytic anaemia.
Oropharyngeal
Causal relationship unknown: A few severe cases of sore throat have been observed.
Other
Less common (1 to 3 %): Thirst.
Less frequent (<1%): Anaphylactoid reactions, menstrual disorder, pyrexia (chills and fever), eosinophilic pneumonitis.
Causal relationship unknown: Angioneurotic oedema, hyperglycaemia, hypoglycaemia, hyperkalaemia.
Interactions
Naproxen may interact with albumin bound medicines e.g. warfarin or bishydroxycoumarin and induce excessively prolonged prothrombin times. Patients receiving hydantoins, sulphonamides, sulphonylureas or methotrexate should be observed for increased effect or toxicity.
The concurrent use of NSAIDs and warfarin has been associated with severe and sometimes fatal haemorrhage. APO-NAPROXEN SR should only be used in combination with warfarin if absolutely necessary and patients taking this combination of therapies should be closely monitored.
Patients who have coagulation disorders or are receiving medication that interferes with haemostatis should be carefully observed of administered naproxen. Patients on full anticoagulation therapy e.g. heparin or dicoumarol derivatives may be at increased risk of bleeding if given naproxen concurrently. The benefits should be weighed against the risks.
Probenecid significantly prolongs the half-life of naproxen. This is associated with a decrease in conjugated metabolites and an increase in 6-o-desmethylnaproxen.
Sodium bicarbonate may enhance the rapidity of naproxen absorption.
Concomitant administration of antacid or cholestyramine can delay the absorption of naproxen but does not affect the extent.
Concomitant administration of food can delay the absorption of naproxen but does not affect the extent.
Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other β-blockers.
The natriuretic effect of frusemide has been reported to be inhibited by some medicines in the class.
Naproxen has been reported to inhibit renal lithium clearance leading to increases in plasma lithium concentration.
In vitro studies have shown that naproxen may interfere with the metabolism of zidovudine resulting in higher zidovudine plasma levels. Consideration should be given to decreasing zidovudine doses to avoid the potential of increased side effects associated with increased zidovudine plasma levels.
Naproxen may increase the risk of renal impairment associated with the use of ACE inhibitors.
Laboratory Tests
Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
Urinary 17-ketogenic steroids may be spuriously increased due to a reaction between naproxen (and/or its metabolites) and m-dinitrobenzene (used in this assay). 17-hydroxycorticosteroid measurements (Porter/Silber test) do not appear to be altered.
Naproxen may interfere with some urinary assays for 5-hydroxyindoleacetic acid.
Overdosage
Symptoms
Significant overdosage may be characterised by drowsiness, epigastric pain, indigestion, nausea or vomiting. A few patients have experienced seizures but it is not clear if these were related to naproxen. It is not known what dose of naproxen would be life-threatening.
Treatment
The stomach should be emptied and the usual supportive measures employed. Animal studies indicate that the prompt administration of activated charcoal would tend to reduce markedly the absorption of the medicine. Due to the sustained release characteristic of APO-NAPROXEN SR it should be expected that naproxen will continue to be absorbed for up to 18 hours after ingestion. Haemodialysis does not decrease the plasma concentration of naproxen due to the high degree of protein binding.
Pharmaceutical Precautions
Shelf life 24 months from date of manufacture
Store below 25°C.
Protect from heat, light and moisture.
Medicine Classification
Prescription Only Medicine
Package Quantities
Bottle packs of 100 and 500 tablets.
Blister packs of 30 and 90 tablets.
Further Information
Tablets contain Sunset Yellow and D&C Yellow #10 as colouring agents.
Name and Address
Apotex NZ Ltd.
32 Hillside Road
Glenfield
Private Bag 102-995
North Shore Mail Centre
Auckland
Telephone: (09) 444-2073
Date of Preparation
21 June 2007