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The use of naproxen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Undesirable effects may be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms. Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.
Effects on the heart, blood circulation, and cerebral circulation: Appropriate monitoring and advice are required for patients with hypertension and/or mild or moderate cardiac failure as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that the use of coxibs and some other anti-inflammatory analgesics may be associated with a small increased risk of arterial thrombotic events (such as myocardial infarction or stroke, which can lead to death). Although current data suggests that the risk may be lower in connection with naproxen use (1,000 mg/day), it cannot be excluded entirely. This risk may appear as early as the first few weeks of taking the drug and may increase over time. The risk of cardiovascular thrombosis is observed mainly at high doses.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be treated with naproxen only after careful consideration. Similar considerations should be made before initiating long-term therapy in patients with risk factors for cardiovascular disease (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Periodic examination for the appearance of cardiovascular events is necessary, even if the patient has no prior cardiovascular symptoms. Patients should be warned of symptoms of serious cardiovascular complications and advised to seek medical attention as soon as symptoms appear.
To minimize the risk of cardiovascular adverse effects, naproxen should be used at the lowest effective daily dose for the shortest possible duration.
Serum potassium concentrations should be monitored especially in patients receiving angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or potassium-sparing diuretics. Anti-inflammatory analgesics may decrease the efficacy of some antihypertensive drugs.
Renal effects: Patients with renal or hepatic failure, hypertension, or cardiac failure, and elderly patients should be monitored for renal function and hemodynamics during naproxen treatment. Naproxen should be avoided, if possible, in patients with moderate renal failure. Naproxen is contraindicated in patients with severe renal impairment (baseline creatinine clearance less than 30 mL/min) or severe hepatic impairment.
Dehydration during the use of an anti-inflammatory analgesic (i.e. NSAID) increases the risk of acute renal failure, so the patient's possible dehydration should be corrected before naproxen treatment is initiated. The naproxen treatment should be started with caution in patients with a history of considerable dehydration. Like other anti-inflammatory analgesics, long-term treatment with naproxen has caused renal papillary necrosis and other pathological renal alterations.
Renal toxicity has also been detected in patients in whom renal prostaglandins maintain renal perfusion. In these patients, the use of anti-inflammatory analgesics may cause a dose-dependent reduction in the formation of prostaglandins, leading to reduced renal perfusion. This may progress into renal failure. The risk is highest in elderly patients, those using diuretics, ACE inhibitors, or angiotensin-II receptor antagonists, and in patients with renal or hepatic impairment or cardiac failure. Discontinuation of treatment usually corrects the patient's status to the pre-treatment level.
Gastrointestinal hemorrhages, ulcers, and perforations: Gastrointestinal 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.
Naproxen reduces thrombocyte activation and aggregation but this effect is transient and lasts less than 48 hours after a single dose. This should be taken into account when treating postoperative patients with an increased risk of hemorrhage, patients on anticoagulant medication, patients with hemophilia, or other patients with diseases impairing the functioning of the coagulation system or with thrombocytopenia. The risk of gastrointestinal haemorrhage increases even by this mechanism.
The risk of GI bleeding, ulceration, or perforation is higher with increasing NSAID doses, in patients with a history of ulcers, particularly if complicated with hemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest possible 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 acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk.
Patients with a history of GI adverse reactions, 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 acetylsalicylic acid.
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 their condition may be exacerbated.
Cutaneous adverse effects: 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. Patients appear to be at the highest risk for these reactions early in the course of therapy: the onset of the reaction occurs 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.
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 angioedema, bronchospastic reactivity (e.g. asthma), rhinitis, and nasal polyps.
Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.
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.
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.
The use of naproxen 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.
Anti-inflammatory analgesics may aggravate bronchospasm in patients with allergic disease.
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.
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. Naproxen is contraindicated in patients with severe hepatic impairment.
Pseudoporphyria (blistering cutaneous photosensitivity) has been reported in up to 10% of pediatric rheumatic patients in connection with naproxen treatment exceeding four weeks. Patients should be monitored for this reversible phenomenon and the use of the preparation should be discontinued if symptoms occur.
The antipyretic and anti-inflammatory activities of naproxen may reduce fever and inflammation, thereby diminishing their utility as diagnostic signs.
Excipients: Naproxen oral suspension contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).
Naproxen oral suspension contains 400 mg/mL sorbitol. Daily doses as per instructions yield 1.6 g-20 g sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Sorbitol may have a mild laxative effect.
This medicinal product contains 0.8 mg/mL sodium, 24 mg sodium per 30 mL dose, which is equivalent to 1.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on Ability to Drive and Use Machines: Usually, naproxen has no influence on the ability to drive and use machines. Occasional adverse effects include tiredness, difficulty in ability to concentrate, dizziness, or visual disturbances. If these symptoms occur, driving a car or using machines should be avoided.
Use in the Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs; especially gastrointestinal bleeding and perforation which may be fatal. Prolonged use of NSAIDs in these patients is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.
