| Underlined text has been added, text with strike through deleted:
4.2 Posology and method of administration
Route of administration
For Ooral administration.
To be taken preferably with or after food.
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 Naprosyn dosing is unknown. As with other drugs used in the elderly it is prudent to use the lowest effective dose and for the shortest duration possible as elderly patients are more prone to adverse events. 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.Special warnings and special precautions for use.
Renal/hepatic impairment
A lower dose should be considered in patients with renal or hepatic impairment. Naprosyn 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.
4.3 Contraindications
Active or history of peptic ulceration or active gastrointestinal bleeding (two or more distinct episodes of proven ulceration or bleeding). History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Hypersensitivity to naproxen, or naproxen sodium, or any of the excipients. formulations. Since the potential exists for cross-sensitivity reactions, Naprosyn should not be given to patients in whom aspirin or other non-steroidal anti-inflammatory/analgesic drugs 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.
Severe renal, hepatic or heart failure.
Naproxen is contraindicated during the last trimester of pregnancy (see Section 4.6).
4.4 Special warnings and precautions for use
Elderly and/or debilitated patients are particularly susceptible to the adverse effects of NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. Prolonged use of NSAIDs in the elderlythese patients is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.
Episodes of gastro-intestinal bleeding have been reported in patients with naproxen therapy. Naprosyn should be given under close supervision to patients with a history of gastro-intestinal disease.
Serious gastro-intestinal adverse reactions, can occur at any time in patients on therapy with non-steroidal anti-inflammatory drugs. The risk of occurrence does not seem to change with duration of therapy. 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 of the serious gastro-intestinal events associated with non-steroidal anti-inflammatory drugs occurred in this patient population.
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.
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.
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 may be at a greater risk when taking Naprosyn.
Gastrointestinal bleeding, ulceration and perforation
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.
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 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 corticosteroid, 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 Naprosyn, 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).
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.
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 and the elderly. Renal function should be monitored in these patients (see also Section 4.3).
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/or creatinine clearance is advised in these patients. Naprosyn is not recommendedcontraindicated in patients having a baseline creatinine clearance of less than 2030ml/minute.
Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding.
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 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Naprosyn should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
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.
4.5 Interaction with other medicinal products and other forms of interaction
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 anti-coagulants (see Section 4.4).
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see Section 4.4).
Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anticoagulants, other NSAIDs, aspirin or a highly protein-bound sulphonamide should be observed for signs of overdosage of these drugs. Patients simultaneously receiving Naprosyn 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 non-steroidal agents of this class.
Caution is advised when Naprosyn is co-administered with diuretics as there can be a decreased diuretic effect. 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
Naproxen and other non-steroidal anti-inflammatory drugs can reduce the anti-hypertensive effect of propranolol and other beta-blockersanti-hypertensives and may increase the risk of renal impairment associated with the use of ACE inhibitors.
As with all NSAIDs, caution should be taken when co-administering with cortico-steroids because of the increased risk of gastrointestinal ulceration or bleeding.
Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking quinolones may have an increased risk of developing convulsions.
There is an increased risk of gastrointestinal bleeding (see Section 4.4) when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.
There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.
There is an 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.
4.6 Pregnancy and lactation
Pregnancy
Congenital abnormalitites 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. As with other drugs of this type, naproxen produces delay in parturition in animals and also affects the human fetal foetal cardiovascular system (closure of ductua ductus arteriosus). Therefore, naproxen should not be used during pregnancy unless clearly needed. Use of Naprosyn in the last trimester of pregnancy is contraindicated (see Section 4.3). 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 fetal foetal circulation and inhibit contractions, with an increased bleeding tendency in both mother and childthus increasing the risk of uterine haemorrhage.
Nursing mothers
Naproxen has been found in the milk of lactating women. The use of Naprosyn should be avoided in patients who are breast-feeding.
See Section 4.4 regarding female fertility.
4.7 Effects on ability to drive and use machines
Some patients may experience drowsiness, dizziness, vertigo, insomnia, fatigue, visual disturbances or depression with the use of Naprosyn. If patients experience these or similar undesirable effects, they should exercise caution in carrying out activities that require alertnessnot drive or operate machinery.
4.8 Undesirable effects
Gastro-intestinal: The more frequent reactions are nausea, vomiting, constipation, diarrohea, dyspepsia, abdominal discomfort and epigastric distress. More serious reactions which may occur occasionally are gastro-intestinal bleeding, peptic ulceration (sometimes with haemorrhage and perforation), non-peptic gastro-intestinal ulceration and colitis. Jaundice, fatal hepatitis, ulcerative stomatitis, abnormal liver function tests, oesophagitis and pancreatitis have been reported rarely.
Dermatological: Skin rashes including fixed drug eruption, itching (pruritis), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, Stevens Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis and photosensitivity reactions (including cases in which the skin resembles porphyria cutanea tarda, "pseudoporphyria") or epidermolysis bullosa-like reactions may occur rarely.
Renal: Including but not limited to glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, hyperkalaemia, raised serum creatinine, renal papillary necrosis and renal failure.
CNS: Convulsions, dizziness, headache, lightheadedness, insomnia, drowsiness, dream abnormalities, depression, vertigo, aseptic meningitis, inability to concentrate and cognitive dysfunction have been reported.
Cardiovascular: Dyspnoea, oedema, palpitations, congestive heart failure and hypertension have been reported.
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).
Oedema, hypertension and cardiac failure have been reported in association with NSAID symptoms (see section 4.4).
Haematological: Thrombocytopenia, granulocytopenia including agranulocytosis, eosinophilia, leucopenia, vasculitis, aplastic anaemia and haemolytic anaemia may occur rarely.
Respiratory: Asthma, eosinophilic pneumonitis and pulmonary oedema.
Reproductive, female: Infertility
Special senses: Tinnitus, hearing disturbances including impairment, visual disturbances, corneal opacity, papillitis, retrobulbar optic neuritis and papilloedema.
Other: Thirst, pyrexia, mild peripheral oedema, malaise, myalgia, muscle weakness. Anaphylactic reactions to naproxen and naproxen sodium formulations including angioneurotic oedema, have been reported in patients with, or without, a history of previous sensitivity reactions to NSAIDs.
The following adverse events have been reported with NSAIDs and with naproxen.
Gastrointestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Heartburn, nausea, vomiting, constipation, diarrhoea, flatulence, dyspepsia, abdominal discomfort and epigastric distress. More serious reactions which may occur are gastro-intestinal bleeding, which is sometimes fatal, particularly in the elderly (see section 4.4), peptic ulceration, perforation, non-peptic gastro-intestinal ulceration, melaena, haematemesis, stomatitis, ulcerative stomatitis, exacerbation of ulcerative colitis and Crohn’s disease (see section 4.4), oesophagitis, gastritis and pancreatitis.
Blood and lymphatic system disorders: Neutropenia, thrombocytopenia, 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, angio-oedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
Metabolic and nutrition disorders: hyperkalaemia.
Psychiatric disorders: Insomnia, dream abnormalities, depression, confusion and hallucinations.
Nervous system disorders: Convulsions, dizziness, headache, lightheadedness, drowsiness, paraesthesia, retrobulbar optic neuritis, inability to concentrate and cognitive dysfunction have been reported. 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, cardiac failure and congestive heart 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: Jaundice, fatal hepatitis and abnormal liver function tests.
Skin and subcutaneous tissue disorders: Skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, Stevens Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, very rarely toxic epidermal necrolysis, 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: Including, but not limited to, glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, raised serum creatinine, renal papillary necrosis and renal failure.
Reproductive system and breast disorders: Female infertility.
General disorders and administration site conditions: Thirst, pyrexia, fatigue and malaise.
4.9 Overdose
Significant overdosage of the drug may be characterised by drowsiness, heartburn, indigestion, nausea, renal dysfunction or vomiting.
Symptoms include headache, heartburn, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, drowsiness, dizziness, tinnitus, fainting. 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.
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 with 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.
Should a patient ingest a large amount of Naprosyn 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 protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.
5.3 Preclinical safety data
None stated. 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 seet 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 know effects of this class of compounds and were demonstrated in pregnant rats with aspirin and indometacin.
|
