The recommended dosage range is from 500 mg to a maximum of 1,000 mg naproxen per day (10 to 20 ml). The oral suspension of naproxen should be shaken gently before use. During long-term use, the dose of naproxen may be adjusted upwards or downwards depending on the patient`s clinical response. A lower daily dose may be sufficient for long-term administration. Morning and evening doses do not need to be the same size and administering the drug more frequently than twice a day usually makes no difference to the response. In patients who tolerate lower doses well, the dose may be increased to 1500 mg/day of naproxen for limited periods of up to 6 months if higher levels of anti-inflammatory/analgesic activity are required. When treating these patients with naproxen 1500 mg/day, the physician should observe an increased clinical benefit sufficient to compensate for the potentially increased risk. Anemia has occurred in patients treated with NSAIDs. This may be due to occult or coarse blood loss, water retention, or an incompletely described effect on erythropoiesis. If a patient treated with naproxen has signs or symptoms of anemia for oral use, monitor haemoglobin or haematocrit. NSAIDs, including naproxen oral suspension, may increase the risk of bleeding. Concomitant use of warfarin and other blood thinners, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) may increase this risk.
Monitor these patients for signs of bleeding [see Drug Interactions (7)]. Distribution Naproxen has a volume of distribution of 0.16 l/kg. At the therapeutic level, naproxen is more than 99% bound to albumin. At naproxen doses greater than 500 mg/day, there is a less than proportional increase in plasma concentrations due to increased clearance due to plasma protein binding saturation at higher doses (mean low point Css 36.5, 49.2 and 56.4 mg/L with daily doses of 500, 1000 and 1500 mg naproxen, respectively). The naproxen anion has been found in the milk of breastfeeding women at a concentration corresponding to approximately 1% of the peak plasma concentration of naproxen [see Use in Certain Populations (8.2)]. Elimination metabolism Naproxen is extensively metabolized to 6-0-desmethylnaproxen in the liver, and parents and metabolites do not induce metabolizing enzymes. Naproxen and 6-0-desmethylnaproxen are metabolised to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0.13 ml / min / kg. Approximately 95% of the naproxen in each dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethylnaproxen (<1%) or their conjugates (66% to 92%).
The plasma half-life of the naproxen anion in humans is between 12 and 17 hours. The corresponding half-lives of naproxen metabolites and conjugates are less than 12 hours, and their excretion rates have been closely consistent with the plasma clearance rate of naproxen. Small amounts, 3% or less of the administered dose, are excreted with the faeces. Metabolites may accumulate in patients with renal impairment [see Warnings and Precautions (5.6)]. Paediatric specific populations In paediatric patients aged 5 to 16 years with arthritis, naproxen plasma levels were found after a single dose of 5 mg/kg oral naproxen suspension [see dosage and administration (2)] similar to those found in normal adults after a 500 mg dose. The terminal half-life appears to be similar in paediatric and adult patients. No pharmacokinetic studies with naproxen have been conducted in paediatric patients less than 5 years of age. Pharmacokinetic parameters appear to be similar following administration of oral naproxen suspension or tablets in paediatric patients. Geriatric studies show that although the total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen increases in the elderly, although the unbound fraction accounts for <1% of the total naproxen concentration. Unbound naproxen concentrations in older subjects were reported to be between 0.12% and 0.19% of the total naproxen concentration, compared to 0.05% to 0.075% in younger subjects. Hepatic impairment The pharmacokinetics of naproxen have not been determined in patients with hepatic impairment. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased.
Renal impairment The pharmacokinetics of naproxen have not been determined in patients with renal impairment. Since naproxen, its metabolites and conjugates are excreted primarily by the kidneys, it is possible for naproxen metabolites to accumulate in renal impairment. Elimination of naproxen is reduced in patients with severe renal impairment. Aspirin Drug Interaction Studies When NSAIDs were administered with aspirin, NSAID protein binding was reduced, although the clearance of free NSAIDs was not altered. The clinical significance of this interaction is unknown. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see drug interactions (7)]. Safety and efficacy in paediatric patients less than 2 years of age have not been established. Paediatric dosage recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies.
Efficacy or dose-response data are insufficient for other paediatric diseases, but experience with polyarticular juvenile idiopathic arthritis and other use experiences have shown that single doses of 2.5 to 5 mg/kg (as oral naproxen suspension) with a total daily dose not exceeding 15 mg/kg/day are well tolerated in paediatric patients over 2 years of age. Heart failure and oedema: Avoid the use of oral naproxen suspension in patients with severe heart failure unless the benefit outweighs the risk of worsening heart failure.
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