Naproxen Tablets Bp 500mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Naproxen Tablets 500mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Naproxen BP 500mg
For excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet for oral use
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis), ankylosing spondylitis, juvenile rheumatoid arthritis, acute gout and acute musculoskeletal disorders (including sprains and strains, direct trauma and lumbosacral pain, cervical spondylitis, tenosynovitis and fibrositis).
4.2 Posology and Method of administration
Naproxen is administered orally, to be taken preferably with or after food.
Adults
Rheumatoid arthritis, osteoarthrosis and ankylosing spondylitis
500mg to 1g per day taken in two doses at 12 hour intervals.
In the following cases a loading dose of 750mg or 1g per day for the acute phase is recommended:
1. Patients with severe night-time pain and/ or morning stiffness.
2. Patients being switched to naproxen from a high dose of another anti-rheumatic compound.
3. Osteoarthrosis where pain is the predominant symptom.
For patients who require 750mg per day, the size of the morning dose and evening doses can be adjusted on the basis of the predominant symptoms i.e. night-time pain or morning stiffness.
Acute Gout
750mg initially, then 250mg every 8 hours until the attack has resolved. Acute Musculoskeletal Disorders 500mg initially, then 250mg at 6 to 8 hour intervals as needed, up to a maximum daily dose after the first day of 1250mg.
Elderly
One study indicated that although the total plasma concentration of naproxen is unchanged the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding for naproxen dosing is unknown. It is considered wise to use the lowest possible dose in the elderly. The patient should be monitored for gastrointestinal bleeding for 4 weeks following initiation of NSAID therapy.
Renal Impairment
Refer to other special warnings and precautions.
Children
Juvenile rheumatoid arthritis
In children over 5 years of age the usual dose is 10mg/kg/ day taken in two doses at 12 hour intervals.
Naproxen is not recommended for use in any other indication under 16 years of age.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
4.3 Contra-indications
Naproxen is contraindicated in patients with a history of peptic ulceration or with an active peptic ulcer and also with hypersensitivity to naproxen or naproxen sodium formulations. Since the potential exists for cross-sensitivity reactions, naproxen should not be given to patients in whom aspirin or other non-steroidal anti-inflammatory/ analgesic drugs induce asthma, rhinitis or urticaria.
Severe heart failure.
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 symptoms (see section 4.2, and GI and cardiovascular risks below).
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 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 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 suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be 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 be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
Gastrointestinal effects
Episodes of gastro-intestinal bleeding have been reported in patients with naproxen therapy. Naproxen should be given under close supervision to patients with a history of gastro-intestinal disease.
Serious gastro-intestinal adverse reactions, including haemorrhage and perforation, can occur at any time in patients on therapy with non-steroidal anti-inflammatory drugs. The risk of their occurrence appears to increase linearly with the duration of use and is probably associated with the use of higher doses of these drugs. Studies to date have not identified any subset of patients not at risk of developing peptic ulcer and bleeding. However, elderly and debilitated patients tolerate gastro-intestinal ulceration or bleeding less well than others; most serious gastro-intestinal events associated with non-steroidal anti-inflammatory drugs occurred in this patient population.
The antipyretic and anti-inflammatory activities of naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.
Sporadic abnormalities in laboratory tests (e.g. liver function tests) have occurred in patients on naproxen therapy, but no definite trend was seen in any test indicating toxicity.
Naproxen decreases platelet aggregation and prolongs bleeding time. The effect should be kept in mind when bleeding times are determined. Patients who have coagulation disorders, or who are receiving drug therapy that interferes with haemostatis, should be carefully observed if they are taking naproxen. Patients on full anticoagulant therapy (e.g. heparin or warfarin) may be at an increased risk of bleeding if given naproxen concurrently. Therefore the benefits should be weighed against these risks.
Mild peripheral oedema has been observed in a few patients receiving naproxen. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function maybe at a greater risk when taking naproxen.
NSAIDs should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with naproxen administration.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use in patients with impaired hepatic function: Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen but the plasma concentration of unbound naproxen is increased. The implication of this finding for naproxen dosing is unknown, but it is prudent to use the lowest effective dose.
Use in patients with impaired renal function: As naproxen is eliminated to a large extent (95%) by urinary excretion via glomerular filtration it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and creatinine clearance is advised in these patients. Naproxen is not recommended in patients having baseline creatinine clearance less than 20ml/ minute.
Certain patients, specifically those whose renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure and pre-existing renal disease, should have renal function assessed before and during naproxen therapy. Some elderly patients in whom impaired renal function may be expected as well as patients using diuretics, may also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.
4.5 Interactions with other Medicaments and other forms of Interaction
Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anticoagulants or a highly protein bound sulphonamide should be observed for signs of over-dosage of these drugs. No interactions have been observed in clinical studies with naproxen sodium or naproxen and anticoagulants or sulphonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class.
The natriuretic effect of frusemide has been reported to be inhibited by some drugs of this class.
Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported.
Naproxen and other non-steroidal anti-inflammatory drugs may antagonise the effects of antihypertensive agents and may increase the risk of renal impairment associated with the use of ACE inhibitors.
Probenecid given concurrently increases naproxen plasma levels and extends its half life considerably.
Caution is advised when methotrexate is administered concurrently because of possible enhancement of its toxicity, since naproxen, among other non-steroidal anti-inflammatory drugs, has been reported to reduce the tubular secretion of methotrexate in an animal model.
There is increased risk of convulsions with 4-quinolone antibacterials when taken with non-steroidal anti-inflammatory agents.
Plicamycin and some cephalosporins may cause hypoprothrombinaemia, increasing the risk of bleeding and ulceration if combined with nonsteroidal anti-inflammatory drugs.
It is suggested that naproxen therapy be temporarily discontinued 48 hours before adrenal function tests are performed because naproxen may artifactually interfere with some tests for 17-ketogenic steroids.
Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.
There is an increased risk of nephrotoxicity when NSAID’s are used in conjunction with diuretics. The diuretic effect may also be reduced.
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels when used in conjunction with cardiac glycosides.
There is an increased risk of nephrotoxicity when cyclosporin is used in conjunction with NSAIDs.
NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
The concomitant use of two or more NSAIDs should be avoided.
The use of corticosteroids with NSAIDs can increase the risk of gastrointestinal bleeding.
4.6 Pregnancy and Lactation
Teratology studies in rats and rabbits, at dose levels equivalent on a human multiple basis to those which have produced foetal abnormality with certain other non-steroidal anti-inflammatory agents, e.g. aspirin, have not produced evidence of foetal damage with naproxen. As with other drugs of this type naproxen delays parturition in animals (the relevance of this finding to human patients is unknown) and also affects the human foetal cardiovascular system (closure of the ductus arteriosus). Good medical practice indicates minimal drug usage in pregnancy and usage of this class of therapeutic agent requires cautious balancing of possible benefit against potential risk to the mother and foetus especially in the first and third trimesters.
Naproxen has been found in the milk of lactating mothers. The use of naproxen should therefore be avoided in patients who are breast feeding.
4.7 Effects on Ability to Drive and Use Machines
None Known.
4.8 Undesirable effects
The most commonly reported adverse reactions on treatment with naproxen are mild, transient gastrointestinal symptoms and effects on the central nervous system.
Frequencies are defined as follows: Common (> 1/100, <1/10); uncommon (>1/1000, >1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000, including isolated reports).
|
Blood and lymphatic system disorders |
Very rare |
Agranulocytosis, eosinophilia, granulocytopenia, leukopenia, thrombocytopenia, pancytopenia |
|
Immune system disorders |
Rare |
Anaphylactic ractions, Quinckes oedema, |
|
allergic and hypersensitivity reactions | ||
|
Metabolism and nutrition disorders |
Uncommon |
Hyperkalaemia |
|
Psychiatric disorders |
Uncommon |
Depression, insomnia, vivid dreams, nightmares, loss of concentration, cognitive dysfunction |
|
Nervous system disorders |
Common |
Headache, dizziness, drowsiness, confusion |
|
Very Rare |
Aseptic meningitis, exacerbation of Parkinsons disease, convulsions | |
|
Eye disorders |
Common |
Visual disturbances |
|
Ear and labyrinth disorders |
Common |
Hearing disturbances, tinnitus |
|
Rare |
Hearing impairment | |
|
Cardiac disorders |
Common |
Oedema, dyspnoea, congestive heart failure |
|
Uncommon |
Palpitations | |
|
Vascular disorders |
Very Rare |
Vasculitis, arterial thrombotic events (for example myocardial infarction or stroke) |
|
Respiratory, thoracic and mediastinal disorders |
Rare |
Exacerbation of asthma |
|
Very Rare |
Eosinophilic pneumonitis | |
|
Gastrointestinal disorders |
Very Common |
abdominal pain and disturbances, heartburn, nausea, constipation |
|
Common |
Diarrhoea, stomatitis, vomiting, dyspepsia | |
|
Uncommon |
Gastrointestinal bleeding or perforation, melaena, haematemesis | |
|
Very Rare |
Gastrointestinal ulceration, colitis, pancreatitis, enlarged salivary glands | |
|
Hepatobiliary disorders |
Uncommon |
Raised liver enzymes, jaundice |
|
Rare |
Toxic hepatitis | |
|
Skin and subcutaneous tissue disorders |
Common |
Pruritis, rash, ecchymosis, purpura, sweating |
|
Uncommon |
Photosensitivity, urticaria | |
|
Rare |
Alopecia, pseudoporphyria | |
|
Very Rare |
Toxic epidermal necrolysis, erythema multiforme and Stevens Johnsons syndrome | |
|
Musculoskeletal and connective tissue disorders |
Rare |
Myalgia, muscle weakness |
|
Renal and urinary disorders |
Very Rare |
Glomerular nephritis, haematuria, interstitial nephritis, nephrotic syndrome, renal insufficiency, renal papillary |
|
necrosis | ||
|
Reproductive system and breast disorders |
Uncommon |
Menstrual disturbances |
|
General disorders and administration site conditions |
Common |
Fatigue |
Peptic ulcer, perforation or gastrointestinal bleeding can be fatal. Ulcerative stomatitis has been reported including exacerbations of colitis and Crohns syndrome.
Oedema, hypertension, and cardiac failure have been reported in association with NSAID treatment.
Clinical trial and epidemiological data suggest that use of 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) (see section 4.4).
4.9 Overdose
Significant overdosage of the drug may be characterised by drowsiness, heartburn, indigestion, nausea or vomiting. A few patients have experienced seizures, but it is not clear whether these were naproxen related or not. It is not known what dose of the drug would be life threatening.
Should a patient ingest a large amount of naproxen accidentally or purposefully, the stomach may be emptied and usual supportive measures employed. Animal studies indicate that the prompt administration of activated charcoal in adequate amounts would tend to reduce markedly the absorption of the drug.
Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiinflammatory and Antirheumatic products, Nonsteroids
ATC code: M01A E02
Naproxen is a non-steroidal anti-inflammatory analgesic of the propionic acid group which has antipyretic activity. Naproxen inhibits the activity of the enzyme cyclooxygenase, which results in decreased formation of the precursors of prostaglandins and thromboxanes from arachidonic acid. While resultant decrease in synthesis and activity of prostaglandins may be responsible for many of the effects of Naproxen, other actions may also contribute to its therapeutic effects.
5.2 Pharmacokinetic Properties
Naproxen is readily absorbed from the gastro-intestinal tract. Peak plasma concentrations are attained 2 to 4 hours after ingestion. At therapeutic concentration naproxen is more than 99% bound to plasma proteins and has a plasma half-life of about 13 hours. Approximately 95% of a dose is excreted in urine as naproxen and 6-0-desmethyl-naproxen and their conjugates. Less than 3% of a dose has been recovered in the faeces. Naproxen crosses the placenta and is excreted in breast milk.
5.3 Preclinical Safety Data
There are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Each tablet contains Lactose, Maize Starch, Povidone K29/32, Polysorbate 80, Sodium Starch Glycollate, Purified Talc, Magnesium Stearate and quinoline yellow (E104).
6.2 Incompatibilities
None Known
6.3 Shelf Life
Blister packs and polypropylene containers: 60 months.
Amber glass bottles: 36 months.
6.4 Special Precautions for Storage
Store in a dry place and at a temperature not exceeding 25°C. Protect from light.
6.5 Nature and Contents of Container
Naproxen Tablets are available in PVC/foil blisters, polypropylene containers with polyethylene caps or amber glass bottles with wadless plastic caps. The pack sizes available in both PVC/foil blisters and polypropylene container pack types are 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168 and 180. In the polypropylene containers pack sizes of 250 and 500 are also available. In the amber glass bottles pack sizes of 100, 250 and 500 are available.
6.6 Instructions for Use/Handling
None
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Ltd t/a Mylan
Station Close
Potters Bar
Herts
EN6 1TL
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0058
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
29 August 1984 / 28 September 2000
10
DATE OF REVISION OF THE TEXT
29/01/2010