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Pharmacology: Pharmacodynamics: Naproxen sodium: Naproxen sodium is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activity by inhibiting cyclooxygenase (COX)-1 and COX-2 isoenzymes resulting in inhibition of prostaglandin synthesis. Pain relief with naproxen sodium usually begins within 30 minutes compared with one hour for plain naproxen.
Paracetamol: Paracetamol exhibits analgesic and antipyretic activity by inhibiting prostaglandin synthesis. It produces analgesia by elevating the pain threshold and antipyresis through its action on the hypothalamic heat regulating center. In therapeutic doses, the analgesic and antipyretic action of paracetamol is comparable to that of aspirin. Paracetamol does not adversely affect platelet function and hemostasis.
Pharmacokinetics: Naproxen sodium: Naproxen and naproxen sodium are readily absorbed from the gastrointestinal (GI) tract. Naproxen sodium is more rapidly absorbed with peak plasma concentrations occurring about one to two hours after oral administration, compared with two to four hours for naproxen. The oral bioavailability of Naproxen sodium is 95%. The rate but not the extent of absorption is decreased when naproxen or naproxen sodium is taken with food.
Naproxen has a volume of distribution of 0.16 L/kg and is more than 99% plasma protein bound. Naproxen plasma concentrations increase proportionately with doses up to 500 mg daily. Increased clearance due to saturation of plasma proteins is seen at higher doses. Naproxen diffuses into synovial fluid, crosses the placenta and is also distributed in small amounts into breast milk. Naproxen's plasma half-life is about 13 hours.
Naproxen is extensively metabolized in the liver, with about 95% of a dose excreted in the urine as naproxen and 6-desmethylnaproxen and their conjugates; less than 5% of a dose is excreted in the feces.
Paracetamol: Paracetamol is rapidly and almost completely absorbed from the GI tract. After oral administration, peak plasma concentrations of paracetamol are attained within 10 to 60 minutes. After 8 hours, only small amounts of the drug are detectable in plasma.
Paracetamol is rapidly and uniformly distributed into most body tissues, except fat. About 10 to 25% of paracetamol in the blood is bound to plasma proteins. Paracetamol has a plasma half-life of 1.25 to 3 hours. It is also metabolized by microsomal enzyme systems in the liver. About 80 to 85% of paracetamol undergoes conjugation predominantly with glucuronic acid and to a lesser extent, with sulfuric acid.
Paracetamol is excreted in the urine mainly as glucuronide with small amounts of sulfate, mercaptate, and unchanged drug. About 85% of the paracetamol dose is excreted as free and conjugated paracetamol within 24 hours after oral administration.
Special Populations: Elderly: Studies demonstrated that the total plasma concentration of naproxen in the elderly is unchanged. However, its unbound plasma fraction is elevated. The clinical significance of this pharmacokinetic alteration is unclear, but it is possible that the increased free naproxen concentration could be related with the increased incidence of adverse events per administered dosage in some elderly patients.
Renal Impairment: Elimination of naproxen sodium is reduced in patients with severe renal impairment. Accumulation of naproxen metabolites and paracetamol conjugates may occur in patients with moderate to severe renal impairment. In addition, severe renal failure reduces the binding of naproxen sodium to serum proteins, resulting to its increased metabolism and volume of distribution in these patients.
Hepatic Impairment: The pharmacokinetics of naproxen sodium in patients with hepatic insufficiency has not been determined. However, chronic alcoholic liver disease or other disease with decreased or abnormal plasma albumin reduce the total plasma levels of naproxen and increase the fraction of unbound naproxen.
The plasma half-life of paracetamol may be prolonged in patients with severe acute and decompensated liver disease.
Bioavailability Study: Naproxen sodium 275 mg + paracetamol 325 mg fixed-dose combination (FDC) tablet was administered in adults under fasting conditions.
Naproxen sodium reached its maximum plasma concentrations (Cmax=58.319 ± 11.4052 mcg/mL) at 0.942 ± 0.6564 hours (Tmax). The total area under the curve from blood level profile from time 0 to 48 hours (AUC0-48h) of naproxen sodium was 783.014 ± 93.5304 mcg·h/mL, while the total area under the plasma concentration curve from time 0 to time infinity (AUC0-∞) was 912.529 ± 122.6362 mcg·h/mL. The mean elimination half-life of naproxen sodium was 17.582 ± 2.3428 hours, and the elimination rate constant was 0.04 ± 0.0052 hr-1.
Paracetamol attained its Cmax (4.695 ± 1.0018 mcg/mL) at 0.875 ± 0.4361 hours. Its AUC0-48h and AUC0-∞ were 18.477 ± 3.6618 mcg·h/mL and 19.211 ± 3.7612 mcg·h/mL, respectively. The mean elimination half-life of paracetamol was 4.862 ± 1.9968 hours, and the elimination rate constant was 0.169 ± 0.0751 hr-1.
