Naproxen 250mg Gastro-Resistant Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Naproxen 250mg Gastro-resistant Tablets Period Pain Reliever 250mg Gastro-resistant Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: 250mg Naproxen.
3 PHARMACEUTICAL FORM
Gastro-resistant tablets.
White, round, biconvex enteric-coated tablets.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Indicated for the treatment of primary dysmenorrhoea in women aged 15 to 50 years.
4.2 Posology and method of administration
For oral administration.
To be taken preferably with or after food swallowed whole with water.
Adolescents (post puberty) and adult females between the ages of 15 and 50:
On the first day 2 tablets (500 mg) should be taken initially and then one tablet (250 mg) after 6 to 8 hours if needed.
On the second and third day, if needed, one tablet (250mg) should be taken every 6 to 8 hours. Not more than 3 tablets to be taken per day. The maximum duration of continuous treatment in any one cycle (period) is 3 days.
Undesirable effects may be minimised by using the lowest effective dose the shortest duration necessary to control symptoms (see section 4.4).
4.3
Contraindications
Hypersensitivity to naproxen, naproxen sodium formulations or any of the other excipients.
Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
History of gastrointestinal bleeding or perforation, related to previous NSAIDs.
Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.
Severe heart failure, renal failure or hepatic failure (see section 4.4).
Use with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
Concomitant use of anticoagulants and antiplatelets (see section 4.5).
Pregnancy and breast-feeding (see section 4.6).
4.4 Special warnings and precautions for use
Period Pain Reliever 250mg Gastro-resistant Tablets should not be taken, except on the advice of a doctor, by women who first experience period pain more than a year after starting menstruation.
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, cardiovascular risks below).
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
Cardiovascular and cerebrovascular effects:
Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension 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 risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggests that the use of naproxen (1000mg daily) may be associated with a lower risk, some risk cannot be excluded. There are insufficient data regarding the effects of low dose naproxen 250mg - 750mg daily to draw firm conclusions on possible thrombotic risks.
Gastrointestinal
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
Although naproxen is usually well tolerated, there have been reported incidences of gastro-intestinal bleeding. Therefore, patients with a history of gastro-intestinal disease should not take naproxen without being closely monitored by their doctor (see section 4.3)
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.
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)
- in the elderly (see section 4.2)
- when used with alcohol
- in smoking
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:
Bronchospasm may be precipitated in patients suffering from or with a previous
history of bronchial asthma or allergic disease Renal:
Renal impairment, as the use of NSAIDs may result in further deterioration of renal function (see sections 4.3 and 4.8)
Patients with renal or cardiac impairment should only use naproxen with great caution and under their doctor’s supervision who will monitor serum creatinine and/or creatinine clearance. When the baseline creatinine is less than 20 ml/min naproxen is not recommended.
When renal blood flow is compromised, patients should have renal function assessed before and during naproxen therapy. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.
Hepatic:
Patients with impaired liver function should only take naproxen under the supervision of their doctor (see sections 4.3 and 4.8). When liver function is impaired, the plasma concentration of unbound naproxen is increased. The significance of this is unknown but caution is advised when high doses are required (see sections 4.3 and 4.8).
Haematological:
Patients who have coagulation disorders or patients who are receiving drug therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered.
Naproxen decreases platelet aggregation and prolongs bleeding time. Patients at high risk of bleeding or those on full anti-coagulation therapy (e.g. dicoumarol derivatives) can be at increased risk of bleeding if given naproxen-containing products.
Anaphylactic (anaphylactoid) reactions:
In susceptible individuals hypersensitivity reactions may occur (see section 4.3) 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 angioedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.
Anaphylactic (anaphylactoid) reactions may have a fatal outcome.
SLE and mixed connective tissue disease:
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease there may be 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: 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.
Ocular effects:
Studies have not shown any changes in the eye attributable to naproxen administration. Rarely, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilledema, 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.
Impaired female fertility:
There is limited evidence that drugs which inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.
The anti-inflammatory and antipyretic activities of naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Steroids:
Patients taking steroids should not take naproxen except under the supervision of their doctor. If steroid dosage is eliminated or reduced 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.
Interference in tests:
Naproxen therapy should be temporarily withdrawn 48 hours before adrenal function tests are performed as it may artifactually interfere with some tests for 17-ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.
Sporadic abnormalities in laboratory tests (e.g. liver function test) have occurred in patients on naproxen therapy, but no definite trend was seen in any test indicating toxicity.
This product contains potassium sorbate, caution should be used in treating patients on a low potassium diet. High blood levels of potassium can cause stomach upsets and diarrhoea.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Label will include:
Read the enclosed leaflet before taking this product.
Do not take if you:
• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding
• are allergic to naproxen or any other ingredients of the product, aspirin or other related painkillers
• are taking other NSAIDpainkillers, or aspirin with a daily dose above 75mg
• are taking medicines that thin the blood
• are pregnant or breastfeeding.
Speak to a pharmacist or your doctor before taking if you:
• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems
• are a smoker
If symptoms persist or worsen, consult your doctor.
4.5 Interaction with other medicinal products and other forms of interaction
Naproxen should be avoided in combination with:
Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.4).
Other NSAIDs including cyclo-oxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.3).
Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.3).
Naproxen should be used with caution in combination with:
Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Naproxen and other non-steriodal anti-inflammatory drugs may increase the risk of renal impairment associated with the use of ACE-inhibitors or angiotensin II receptor antagonists. Diuretics can increase the risk on nephrotoxity of NSAIDs.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increase risk of gastrointestinal bleeding (see section 4.4).
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: There is evidence for potential increases in plasma levels of lithium, due to decreased elimination of lithium.
Methotrexate: There is a potential for an increase in plasma methotrexate, due to decreased elimination of methotrexate.
Ciclosporin: Increased risk of nephrotoxicity.
Probencid: may increase plasma levels and extend the half-life of some NSAIDs.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone,
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 haemarthoroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
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.
Bisphosphonates: concomitant use of bisphosphonates and NSAIDs may increase the risk of gastric mucosal damage.
Colestyramine: colestyramine delays the absorption of naproxen. Naproxen should be taken at least one hour before or four to six hours after colestyramine.
Naproxen is highly protein-bound to plasma proteins and if anti-coagulants, or hydantoins e.g. phenytoin are given simultaneously, overdosage of these drugs may result.
4.6 Pregnancy and lactation
Naproxen should not be used during pregnancy or breast-feeding except on the advice of a doctor.
Whilst no teratogenic effects have been demonstrated in animal toxicology studies, the use of naproxen during pregnancy should if possible be avoided. Congenital abnormalities have been reported in association with naproxen 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 (a closure of ductus arteriosus), use in pregnancy should be avoided. In the limited studies so far available, naproxen appears in the breast milk in very low concentrations and is unlikely to adversely affect the breast-fed infant. However, the use of naproxen should be avoided in patients who are breast feeding.
See section 4.4 Special warnings and precautions for use, regarding female fertility.
4.7 Effects on ability to drive and use machines
Usually there is no effect at the recommended low dose and short duration of treatment. However dizziness, drowsiness, vertigo, insomnia, depression or visual disturbances are possible undesirable effects after taking NSAIDs. If affected, patients should not drive or operate machinery.
4.8 Undesirable effects
Gastro-intestinal: the most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (See section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis exacerbation of colitis and Crohn’s disease (See section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Hypersensitivity: Hypersensitivity reactions have been reported following treatment with 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, pruritis, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme.
Cardiovascular: 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).
Other adverse events reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.
Hepatic: Abnormal liver function, hepatitis and jaundice.
Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune 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), depression, confusion, hallucinations, tinnitus, hearing impairment, vertigo, dizziness, malaise, fatigue and drowsiness.
Haematological: Thrombocytopenia, neutropenia, agranulocytosis, granulocytopenia, aplastic anaemia and haemolytic anaemia. Eosinophilic pneumonitis, hyperkalaemia, have also been reported rarely with some NSAIDs.
Dermatological: Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare). Photosensitivity reactions, alopecia, angioedema.
4.9 Overdose
Symptoms
Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central neverous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time / INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.
Management
Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents with 1 hour of ingestion of a potentially toxic amount. If frequent of prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.
Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Naproxen is a non-steroidal anti-inflammatory agent.
Naproxen reduces the synthesis of prostaglandins primarily by inhibiting the enzyme cyclo-oxygenase. Naproxen has been shown to have antiinflammatory activity in a number of experimental models. Naproxen inhibits prostaglandin E2 synthesis in vitro by human rheumatoid synovial microsomes. It also inhibits prostaglandin E2 production by phytohaemagglutin-stimulated peripheral blood mononuclear cells. At 10'4 M (23mg.1-1) naproxen inhibits neutral protease activity derived from human polymorphonuclear leucocytes. Naproxen also inhibits in vitro the activity of cathepsin-P and other hydrolytic enzymes derived from lysosomes. Naproxen is a potent in inhibitor of leucocyte migration and produces effects comparable to those of colchicine.
5.2 Pharmacokinetic properties
Naproxen is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are attained 2-4 hours after ingestion. Plasma concentrations of naproxen increase proportionally with dose up to about 500mg daily; at higher doses there is an increase in clearance caused by saturation of plasma proteins. At therapeutic concentrations 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-O-desmethylnaproxen 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 pre-clinical 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
Methacrylic acid-ethylacrylate copolymer (1:1) Lactose
Magnesium stearate
Maize starch Crospovidone Propylene glycol Sodium hydroxide Triethyl citrate Titanium dioxide (E171) Potassium sorbate (E202) Sodium citrate (E331)
Xanthan gum (E415) Hydroxypropyl cellulose (E463) Purified talc (E553)
Beeswax
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Shelf-life
36 months from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package.
6.5 Nature and contents of container
PVC/PVdC/Aluminium blister. Pack sizes of 3,6,8,9 tablets. (Not all pack sizes will be marketed).
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjordur Iceland.
MARKETING AUTHORISATION NUMBER(S)
8
PL 30306/0226
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/06/2009
10 DATE OF REVISION OF THE TEXT
23/05/2012