Bio-Naproxen Tablets

Treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. BIO-NAPROXEN may also be used in the treatment of acute gout, mild to moderate pain, associated with primary dysmenorrhoea, bursitis and acute tendonitis.

BIO-NAPROXEN should not be used in children under the age of 16 years.

Adults

• Rheumatoid arthritis, osteo-arthritis and ankylosing spondylitis: 250 to 375 mg twice daily with food.
• Acute gout: An initial dose of 750 mg with meals, followed by 250 mg every 8 hours until the attack has subsided.
• Mild to moderate pain associated with primary dysmenorrhoea, bursitis and acute tendonitis: An initial dose of 500 mg followed by 250 mg every 6 to 8 hours with food.

Use the lowest effective dose for the shortest possible duration of treatment.

• Hypersensitivity or allergic reactions to medicines containing naproxen or naproxen sodium, aspirin or other non-steroidal anti-inflammatory agents.
• Patients in whom aspirin or other non-steroidal anti-inflammatory / analgesic medicines induce the syndrome of asthma, rhinitis, nasal polyps or urticaria. These reactions have the potential of being fatal. Severe anaphylactic-like reactions to naproxen have been reported in such patients.
• BIO-NAPROXEN should not be used in pregnant women or mothers breastfeeding their infants.
• Heart failure.
• History of gastrointestinal perforation, ulceration or bleeding (PUBs) related to previous NSAIDs.
• Active or history of recurrent ulcer/haemorrhage/perforations.
• Porphyria.
• Children: BIO-NAPROXEN is not recommended for use in children under the age of 16 years.
• Severe renal function impairment: BIO-NAPROXEN is not recommended in patients with baseline creatinine clearance of less than 20 ml/minute because accumulation of naproxen metabolites has been seen in such patients (see section 4.4).

BIO-NAPROXEN should be used with special care in patients with gastrointestinal bleeding, with a history of bronchospasm (asthma), with impaired renal or liver function and elderly patients or patients with cardiovascular disease. 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).

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 BIO-NAPROXEN therapy. In view of BIO-NAPROXENu2019s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patient. 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 BIO-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 disease (e.g., hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with BIO-NAPROXEN 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 BIO-NAPROXEN doses
• in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3)
• in the elderly
• when used with alcohol
• in smoking

These patients should commence BIO-NAPROXEN treatment on the lowest dose available. Combination therapy with protective medicine (e.g., misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other medicines likely to increase gastrointestinal risk (see below and section 4.5). Patients with a history of GI toxicity, particularly the 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 antiplatelet medicine such as aspirin (see section 4.5). When GI bleeding or ulceration occurs in patients receiving BIO-NAPROXEN, the treatment should be withdrawn.

BIO-NAPROXEN should be given with caution to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohnu2019s disease, hiatus hernia, gastro-oesophageal reflux disease, angiodysplasia) as these condition may be exacerbated (see section 4.8). The risk of gastrointestinal perforation, ulceration or bleeding (PUBs) is higher with increasing dose and duration of BIO-NAPROXEN treatment, in patients with a history of ulcers, and the elderly. When gastrointestinal bleeding or ulceration occurs in patients receiving BIO-NAPROXEN, treatment with BIO-NAPROXEN should be stopped.

Cardiovascular, renal and hepatic impairment

The administration of BIO-NAPROXEN 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 and the elderly. Renal function should be monitored in these patients (see also section 4.3).

Impaired renal function

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. BIO-NAPROXEN should be used with caution in patients with impaired renal function or a history of kidney disease, especially if long-term usage is considered as BIO-NAPROXEN is an inhibitor of prostaglandin synthesis. Severe hypokalaemia and renal tubular acidosis have been reported due to prolonged use of naproxen as contained in BIO-NAPROXEN at higher than recommended doses. Presenting signs and symptoms included reduced level of consciousness and generalised weakness. Naproxen i.e., BIO-NAPROXEN induced renal tubular acidosis should be considered in patients with unexplained hypokalaemia and metabolic acidosis. Caution should be taken in patients with conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins play a supportive role in the maintenance of renal perfusion. In these patients administration of BIO-NAPROXEN may lead to a dose-dependent reduction in renal prostaglandin formation and may cause overt renal decompensation or failure. Patients with the greatest risk of developing this reaction are those with impaired renal function, hypovolaemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and the elderly. Discontinuation of BIO-NAPROXEN is generally followed by recovery to the pre-treatment state.

BIO-NAPROXEN should be used with great caution where there is impairment of renal function as it is eliminated to a large extent (95 %) via glomerular filtration; the monitoring of serum creatinine and/or creatinine clearance should be conducted in these patients. BIO-NAPROXEN should be used with great caution in these patients and the close monitoring of serum creatinine and/or creatinine clearance is recommended. BIO-NAPROXEN is not recommended in patients having baseline creatinine clearance of less than 20 ml/min. Certain patients, specifically those whose renal blood flow is compromised, because of 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 BIO-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 BIO-NAPROXEN metabolites in these patients.

Impaired liver function

Elevations of one or more liver function tests may occur. Hepatic abnormalities could 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. Cross-reactivity has been reported. 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 BIO-NAPROXEN dosing is unknown but it is prudent to use the lowest effective dose. BIO-NAPROXEN should be used with caution in patients with a history of, or in those with impaired liver function.

Naproxen is highly protein-bound hence patients receiving hydantoins, anticoagulants or a highly protein-bound sulfonamide should be closely monitored for signs of overdosage of this medicine. No interactions have been observed in clinical studies with naproxen or sulfonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal medicines of this class.

NSAIDs: use of two or more NSAIDs concomitantly could result in an increase in side effects. NSAIDs, including BIO-NAPROXEN, have been reported to increase steady state plasma lithium levels by inhibition of renal lithium clearance. Decreased elimination of lithium. It is recommended that these levels are monitored whenever initiating, adjusting or discontinuing naproxen.

Anti-hypertensives: Reduced anti-hypertensive effect. Concomitant administration of BIO-NAPROXEN with beta blockers may reduce their antihypertensive effect and may increase the risk of renal impairment associated with the use of ACE inhibitors or angiotensin II receptor antagonists.

Probenecid: during concurrent administration caution is advised as it increases naproxen plasma levels and extends its half-life considerably.

Decreased elimination of methotrexate: Caution is advised when methotrexate is administered concurrently, due to the possible enhancement of its toxicity as BIO-NAPROXEN, like other NSAIDs has been reported to reduce tubular secretion of methotrexate in an animal model.

Furosemide: The natriuretic effect of furosemide has been reported to be inhibited by some medicine of this class. NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.

Ciclosporin: As with all NSAIDs, caution 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 the effects of mifepristone.

Corticosteroids: As with all NSAIDs, caution should be taken when co-administered with corticosteroids because of the increased risk of gastrointestinal ulceration or bleeding (see section 4.4).

Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).

Acetylsalicylic acid: Clinical pharmacodynamic data suggest that concomitant BIO-NAPROXEN usage for more than one day consecutively may inhibit the effect of low-dose acetylsalicylic acid on platelet activity and this inhibition may persist for up to several days after stopping BIO-NAPROXEN therapy. The clinical relevance of this interaction is not known.

Diuretics: NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g., dehydrated patients or elderly patients) when angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated, and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Anti-coagulants: BIO-NAPROXEN may enhance the effects of anti-coagulants such as warfarin (see section 4.4).

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolone may have an increased risk of developing convulsions.

Anti-platelet medicines and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

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 haem arthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Bisphosphonates: concomitant use of bisphosphonates and NSAIDs may increase the risk of gastric mucosal damage.

Antacids or cholestyramine: the concurrent administration with BIO-NAPROXEN can delay the absorption of BIO-NAPROXEN. BIO-NAPROXEN should be taken at least one hour before or four to six hours after cholestyramine.

Food: concomitant administration can delay the absorption of BIO-NAPROXEN but does not affect the extent thereof.

Lithium: inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has been reported.

Cardiac glycosides: increased plasma concentrations of digoxin have been reported.

ACE inhibitors and potassium-sparing diuretics: concomitant administration may increase the risk of hyperkalaemia.

Thyroid function tests: BIO-NAPROXEN may interfere with thyroid function tests by lowering serum thyroid hormone concentrations.

Adrenal function tests: it is advised that BIO-NAPROXEN therapy should be temporarily discontinued 48 hours before these tests are performed. BIO-NAPROXEN may artifactually interfere with some tests for 17-ketogenic steroids. BIO-NAPROXEN may similarly interfere with some urinary assays of 5-hydroxyindoleacetic acid (5-HIAA).

Aspirin: Plasma concentrations of BIO-NAPROXEN are significantly decreased by concomitant administration of therapeutic doses of aspirin.

Thiazide diuretics, beta-adrenergic antagonists, prazosin and captopril: BIO-NAPROXEN may reduce the diuretic, natriuretic and anti-hypertensive effects of these medicines, due to the inhibition of synthesis of renal prostaglandins.

Pregnancy

The safety and efficacy of BIO-NAPROXEN in pregnancy and lactation has not yet been established. Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1.5 %. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

During the first and second trimester of pregnancy, BIO-NAPROXEN should not be given unless clearly necessary. If BIO-NAPROXEN is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-hydramniosis;
• the mother and the neonate, at the end of pregnancy to:
• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently BIO-NAPROXEN is contraindicated during the last trimester of pregnancy.

Breastfeeding

BIO-NAPROXEN crosses the placenta and has been found in the milk of lactating mothers. In limited studies so far available, BIO-NAPROXEN can appear in breast milk in very low concentrations. BIO-NAPROXEN should be avoided when breastfeeding.

Fertility

If BIO-NAPROXEN is administered to woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and the duration of treatment as short as possible. See section 4.4 for use regarding female fertility.

Undesirable effects such as drowsiness, dizziness, fatigue and visual disturbances are possible after taking BIO-NAPROXEN. If affected, patients should not drive or operate machinery.

System organ class

Symptoms

Headache, vomiting, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible. Prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness (see section 4.4 and section 4.8).

Treatment

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. 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.