Naproxen

NAPROXEN- naproxen tablet, delayed release
STAT Rx USA LLC

Cardiovascular Risk

  • NSAIDs* may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).
  • Naproxen delayed-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

  • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

* Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.

DESCRIPTION

Naproxen is a propionic acid derivative related to the arylacetic acid group of non-steroidal anti-inflammatory drugs.

The chemical name for naproxen is (+)-6-methoxy-α-methyl-2-naphthaleneacetic acid. It has the following structural formula:

naproxen structural formula

C14 H14 O3 M.W. 230.26

Naproxen is a practically odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8.

Naproxen delayed-release tablets USP are available as enteric-coated, white to off-white tablets containing 375 mg or 500 mg of naproxen for oral administration. The inactive ingredients are: corn starch, croscarmellose sodium, FD&C Blue No. 2, magnesium stearate, methacrylic acid copolymer-dispersion, povidone, talc, titanium dioxide, and triethyl citrate. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Naproxen is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The different dosage forms of naproxen are bioequivalent in terms of extent of absorption (AUC) and peak concentration (Cmax ); however, the products do differ in their pattern of absorption. These differences between naproxen products are related to both the chemical form of naproxen used and its formulation. Even with the observed differences in pattern of absorption, the elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. This suggests that the differences in pattern of release play only a negligible role in the attainment of steady-state plasma levels.

Absorption

Delayed release

Naproxen delayed-release tablets are designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for naproxen delayed-release tablets dissolves above pH 6. When naproxen delayed-release tablets were given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled naproxen delayed-release tablets demonstrated that naproxen delayed-release tablets dissolve primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied.

When naproxen delayed-release tablets and naproxen tablets were given to fasted subjects (n = 24) in a crossover study following 1 week of dosing, differences in time to peak plasma levels (Tmax ) were observed, but there were no differences in total absorption as measured by Cmax and AUC:

*
Mean value (coefficient of variation)

Naproxen Delayed-Release Tablets *

500 mg bid

Naproxen Tablets *

500 mg bid

Cmax (mcg/mL) 94.9 (18%) 97.4 (13%)
Tmax (hours) 4 (39%) 1.9 (61%)
AUC0-12 hr (mcg•hr/mL) 845 (20%) 767 (15%)
Antacid effects

When naproxen delayed-release tablets were given as a single dose with antacid (54 mEq buffering capacity), the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly.

Food effects

When naproxen delayed-release tablets were given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax ), but did not affect peak naproxen levels (Cmax ).

Distribution

Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2, and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS , Nursing Mothers).

Metabolism

Naproxen is extensively metabolized in the liver to 6-O -desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-O -desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites.

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