Naproxen Tablets Bp 250mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Naproxen Tablets BP 250 mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Naproxen BP 250 mg per tablet
3 PHARMACEUTICAL FORM
Naproxen tablets BP 250 mg are presented as yellow circular normal convex tablets engraved with company logo on one face and A453 and a break-line on the other face.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the treatment of rheumatoid arthritis, osteoarthrosis, ankylosing spondylitis, juvenile rheumatoid arthritis, acute gout and acute musculoskeletal disorders.
4.2 Posology and method of administration
For oral administration
To be taken preferably with or after food.
Adults
Rheumatoid arthritis, osteoarthrosis and ankylosing spondylitis:
500 mg to 1 gram in two doses at 12-hour intervals or alternatively as a single administration. In the following cases a loading dose of 750 mg or 1 g per day for the acute phase is recommended:
a) In patients reporting severe night-time pain/or morning stiffness.
b) In patients being switched to naproxen from a high dose of another anti-rheumatic compound.
c) In osteoarthrosis where pain is the predominant symptom.
Acute gout: 750 mg at once then 250 mg every eight hours until the attack has passed. Acute musculoskeletal disorders:
500 mg initially followed by 250 mg at 6 to 8 hour intervals with a maximum daily dose after the first day of 1250 mg.
Elderly
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for naproxen dosing is unknown. The elderly are at increased risk of the serious consequences of adverse reactions.
If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. For the effect of reduced elimination in the elderly refer to section 4.4
Children over 5 years;
For the treatment of juvenile rheumatoid arthritis the usual dosage is 10 mg/kg body-weight/day taken in two doses, at 12 hour intervals.
Naproxen tablets are not recommended for use in any other indication in children under 16 years of age.
Renal/hepatic impairment:
A lower dose should be considered in patients with renal or hepatic impairment. Naproxen is contraindicated in patients with baseline creatinine clearance less than 30 ml/minute because accumulation of naproxen metabolites has been seen in patients with severe renal failure or those on dialysis (see section 4.3).
Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.
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
Hypersensitivity to naproxen, naproxen sodium or to any of the excipients.
Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, nasal polyps or urticaria) in response to ibuprofen, aspirin, or other non-steroidal antiinflammatory drugs/ analgesic drugs. These reactions have the potential of being fatal. Severe anaphylactic-like reactions to naproxen have been reported in such patients.
Severe heart failure, hepatic failure and renal failure (see section 4.4).
During the last trimester of pregnancy (see section 4.6)
History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
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). Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.
The use of naproxen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
Elderly:
The elderly and/ or debilitated patients have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2). Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.
The antipyretic and anti-inflammatory activities of Naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
As with other non-steroidal anti-inflammatory drugs, 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 drug as with other non-steroidal anti-inflammatory drugs. Cross reactivity has been reported.
Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking Naproxen.
Gastrointestinal bleeding, ulceration and perforation:
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution should be 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 (see section 4.5)
When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see section 4.8).
Respiratory disorders:
Caution is required if administered to patients suffering from, or with a previous history of bronchial asthma or allergic disease, since NSAIDs have been reported to cause bronchospasm in such patients.
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.
Cardiovascular, Renal and Hepatic Impairment :
Renal failure linked to reduced prostaglandin production The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics, angiotensin converting enzyme inhibitors, angiotensin-II receptor antagonists and the elderly. Renal function should be monitored in these patients (see also section 4.3).
Use in patients with impaired renal function
Assessment of renal function before and during naproxen therapy is advised for those patients in whom renal blood flow may be compromised. As naproxen is eliminated mainly (95%) by urinary excretion via glomerular filtration it should be used with great caution in patients with impaired renal function. Monitoring of serum creatinine and/or creatinine clearance is advised and patients should be adequately hydrated. Naproxen should not be used in patients having a baseline creatinine clearance less than 30 ml/min.
Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding.
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.
Use in patients with impaired liver function
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduces the total plasma concentration of naproxen while increasing the concentration of unbound drug (Naproxen). The implication of this finding for Naproxen dosing is unknown, It is therefore prudent to use the lowest effective dose in patients with impaired hepatic function.
Haematological
Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered.
Patients at high risk of bleeding or those on full anti-coagulation therapy (e.g. dicoumarol derivatives) may be at increased risk of bleeding if given naproxen-containing products concurrently.
Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.
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 drugs or naproxen-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.
Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
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.
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).
SLE and mixed connective tissue disease:
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).
Dermatological:
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Naproxen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Impaired female fertility:
The use of naproxen, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of naproxen should be considered.
Combination with other NSAIDs
The combination of naproxen-containing products and other NSAIDs, including cyclooxygenase-2 selective inhibitors, is not recommended, because of the cumulative risks of inducing serious NSAID related adverse events.
The tablets contain sunset yellow E110 which may cause allergic reactions.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine as it contains lactose.
4.5 Interaction with other medicinal products and other forms of interaction
Prolonged concurrent use of acetaminophen with an NSAID may increase the risk of adverse renal effects. Patients receiving such combined therapy should be kept under close medical supervision.
As naproxen is strongly bound to plasma proteins, patients receiving concurrent treatment with hydantoins, anticoagulants, other NSAIDs, aspirin or highly protein bound sulfonamides should be observed for overdosage of these drugs. Patients simultaneously receiving Naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. No interactions have been observed in clinical studies with naproxen and anticoagulants or sulphonylureas, but caution is nevertheless advised since interaction has been seen with other nonsteroidal agents of this class.
Corticosteroids: as with all NSAIDs, caution should be taken when coadministering with corticosteroids because of the increased risk of GI bleeding or ulceration (see section 4.4).
Anticoagulants: It is considered unsafe to take NSAIDs in combination with anti-coagulants such as warfarin or heparin unless under direct medical supervision, as NSAIDs may enhance the effects of anticoagulants (see section 4.4).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).
Diuretics: concurrent use with an NSAID may decrease diuretic, natriuretic and antihypertensive effects of diuretics, probably by inhibiting renal prostaglandin synthesis. The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Anti-hypertensives including propranolol and beta-blockers: Naproxen and other non-steroidal anti-inflammatory drugs can reduce the anti-hypertensive effect of anti-hypertensives. Concomitant use of NSAIDs with ACE inhibitors or angiotensin-II receptor antagonists may increase the risk of renal impairment, especially in patients with pre-existing poor renal function (See Section 4.4).
Other analgesics including cyclooxygenase-2 selective inhibitors: avoid concomitant use of two or more NSAIDs (including aspirin) as this may result in an increased risk of adverse reactions (see section 4.4).
Lithium: decreased elimination (renal clearance) of lithium leading to increases in plasma lithium concentrations has also been reported.
Methotrexate: Naproxen among other non-steroidal anti-inflammatory drugs may decrease the renal clearance of methotrexate leading to increased methotrexate plasma concentration and risk of toxicity.
Probenecid: Naproxen plasma levels are increased and its plasma half-life extended by the concurrent administration of probenecid.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels
Ciclosporin: as with all NSAIDs, caution should is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration, as NSAIDs can reduce its effect.
Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Zidovudine: increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Naproxen and other NSAID’s may increase the risk of serious haematologic adverse effects when used concurrently with bone marrow depressants or radiation therapy. Since naproxen may interfere with some tests for 17-ketogenic steroids its therapy should be temporarily discontinued 48 hours before adrenal function tests are performed.
Naproxen may also interfere with some assays of urinary 5-hydroxyindoleacetic acid.
Concomitant administration of antacid or colestyramine 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.
4.6 Fertility, pregnancy and lactation
Pregnancy:
Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. NSAIDs should not be used during the first two trimesters of pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.
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 contractions, with an increased bleeding tendency in both mother and child. The onset of labour may be delayed and the duration increased.
Lactation:
In the limited studies so far available, NSAIDs can appear in breast milk in very low concentration. NSAIDs should, if possible, be avoided when breastfeeding.
See section 4.4 Special warnings and precautions for use, regarding female fertility.
4.7 Effects on ability to drive and use machines
Undesirable effects such as dizziness, drowsiness, vertigo, insomnia, depression, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
4.8 Undesirable effects
The following adverse events have been reported with NSAIDs and with naproxen.
Gastrointestinal disorders: The most commonly observed adverse events are gastro-intestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, heartburn, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain (abdominal discomfort), epigastric distress, inflammation, ulceration, perforation and obstruction of the upper and lower gastrointestinal tract, melaena, haematemesis, stomatitis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) and oesophagitis have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Blood and lymphatic system disorders: Thrombocytopenia, neutropenia, granulocytopenia including agranulocytosis, eosinophilia, leucopenia, aplastic anaemia and haemolytic anaemia.
Immune system disorders: Hypersensitivity reactions have been reported following treatment with NSAIDs in patients with, or without, a history of previous hypersensitivity reactions to NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
Metabolism and nutrition disorders: Hyperkalaemia.
Psychiatric disorders: Insomnia, dream abnormalities, depression, confusion, hallucinations.
Nervous system disorders: Headache, dizziness, drowsiness, convulsions, lightheadedness inability to concentrate and cognitive dysfunction, retrobulbar optic neuritis, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4).
Eye disorders: Visual disturbances, corneal opacity, papillitis and papilloedema.
Ear and Labyrinth disorders: Tinnitus, hearing disturbances including impairment and vertigo.
Cardiac disorders: Oedema, palpitations, congestive heart failure and cardiac failure have been reported.
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) (see section 4.4).
Vascular disorders: Hypertension, vasculitis.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, asthma, eosinophilic pneumonitis and pulmonary oedema.
Hepatobiliary disorders: Abnormal liver function tests, fatal hepatitis and jaundice.
Skin and subcutaneous tissue disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating.
Alopecia. erythema multiforme, bullous reactions including Stevens-Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, and Toxic Epidermal Necrolysis (very rare), photosensitivity reactions (including cases in which skin resembles porphyria cutanea tarda “pseudoporphyria”) or epidermolysis bullosa-like reactions which may occur rarely.
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 and muscle weakness.
Renal and urinary disorders: NSAIDs have been reported to cause nephrotoxicity in various forms. Their use can cause interstitial nephritis, nephrotic syndrome, renal failure, nephropathy, haematuria. glomerular nephritis, raised serum creatinine and renal papillary necrosis.
Reproductive system and breast disorders: Female infertility.
General disorders and administration site conditions: Thirst, pyrexia, fatigue and malaise.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
a) Symptoms
Symptoms include headache, heartburn, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
Respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.
In one case of naproxen overdose, transient prolongation of the prothrombin time due to hypothrombinaemia may have been due to selective inhibition of the synthesis of vitamin-K dependent clotting factors.
A few patients have experienced seizures, but it is not known whether these were naproxen-related or not. It is not known what dose of the drug would be life-threatening.
b) Therapeutic measures
Patients should be treated symptomatically as required.
Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.
Good urine output should be ensured.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts.
Frequent or prolonged convulsions should be treated with intravenous diazepam.
Other measures may be indicated by the patient’s clinical condition.
Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of 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
Naproxen has analgesic, anti-inflammatory, and antipyretic properties; it is an inhibitor of prostaglandin synthetase.
Both naproxen and naproxen sodium are used in rheumatic disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, in mild to moderate pain such as dysmenorrhoea, migraine, and some musculoskeletal disorders, and in acute gout.
In ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, the usual dose of naproxen or naproxen sodium is the equivalent of 500 mg to 1 g of naproxen daily in 2 divided doses. A dose of 10 mg per kg body-weight daily of naproxen in 2 divided doses has been used in children over 5 years of age with juvenile rheumatoid arthritis.
In painful conditions such as dysmenorrhoea the usual initial dose is the equivalent of 500 mg naproxen followed by 250 mg every 6 or 8 hours. In acute gout an initial dose equivalent to 750 mg or naproxen followed by 250 mg every 8 hours has been suggested.
Rectal administration of naproxen is sometimes employed.
Naproxen has also been used orally as the piperazine salt.
5.2 Pharmacokinetic properties
Naproxen is readily absorbed when administered orally. The rapidity, but not the extent, of absorption is influenced by the presence of food in the stomach. Peak concentrations in plasma occur within 2 to 4 hours and may be achieved more rapidly after the administration of naproxen sodium. Absorption may be accelerated by the concurrent administration of sodium bicarbonate or reduced by magnesium oxide or aluminium hydroxide. Naproxen is also absorbed rectally, but peak concentrations in plasma are achieved more slowly. The half-life of naproxen in plasma is about 14 hours.
Naproxen and its metabolites are almost entirely excreted in the urine. About 30% of the drug undergoes 6-demethylation, and most of this metabolite, as well as naproxen itself, is excreted as the glucuronide or other conjugates. Naproxen is almost completely (99%) bound to plasma protein following normal therapeutic doses.
Naproxen crosses the placenta and appears in the milk of lactating women at approximately 1 % of the maternal plasma concentration.
5.3 Preclinical safety data
Carcinogenicity
Naproxen was administered with food to Sprague-Dawley rats for 24 months at doses of 8, 16 and 24mg/kg/day. Naproxen 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
Naproxen 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
Naproxen was not teratogenic when administered orally at does of 20mg/kg/day during organogenesis to rats and rabbits.
Perinatal/Postnatal Reproduction
Oral administration of naproxen to pregnant rats at doses of 2, 10 and 20mg/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 indometacin.
6.1 List of excipients
Lactose Maize starch Povidone Purified water Quinoline yellow (E104) Sunset yellow FCF (E110) Sodium starch glycollate Magnesium stearate
6.2 Incompatibilities
None
6.3 Shelf life
3 years in opaque plastic containers 3 years in Al/PVC blister packs
6.4 Special precautions for storage
Protect from heat, light and moisture.
Keep out of the reach of children.
6.5 Nature and contents of container
Opaque plastic containers in pack sizes of 28, 42, 50, 56, 84, 100, 112, 250, 500 and 1000 tablets.
Al/PVC blister packs containing 28, 42, 56, 84 & 112 tablets.
6.6 Special precautions for disposal
No special instructions for use/handling.
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited Units 3 and 4
Quidhampton Business Units Polhampton Lane Overton
Hants RG25 3ED United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20416/0111
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 28/05/2004 Date of renewal of the authorisation: 05/01/09
10 DATE OF REVISION OF THE TEXT
01/05/2014