Vioxx

[Rofecoxib]

Clinical Pharmacology
*IMPORTANT! On Sept. 30, 2004 Merck & Co., Inc. announced a voluntary worldwide withdrawal of VIOXX® (rofecoxib). Please be aware that the information below is provided only for reference.

CLINICAL PHARMACOLOGY

Mechanism of Action

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VIOXX is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of VIOXX is believed to be due to inhibition of prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2). At therapeutic concentrations in humans, VIOXX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme.

Pharmacokinetics

Absorption

The mean oral bioavailability of VIOXX at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%. The area under the curve (AUC) and peak plasma level (Cmax) following a single 25-mg dose were 3286 (± 843) ng° hr/ mL and 207 (± 111) ng/ mL, respectively. Both Cmax and AUC are roughly dose proportional across the clinical dose range. At doses greater than 50 mg, there is a less than proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. The plasma concentration-time profile exhibited multiple peaks.

The median time to maximal concentration (Tmax), as assessed in nine pharmacokinetic studies, is 2 to 3 hours. Individual Tmax values in these studies ranged between 2 to 9 hours. This may not reflect rate of absorption as Tmax may occur as a secondary peak in some individuals. With multiple dosing, steady-state conditions are reached by Day 4. The AUC0-24hr and Cmax at steady state after multiple doses of 25 mg rofecoxib was 4018 (± 1140) ng° hr/ mL and 321 (± 104) ng/ mL, respectively. The accumulation factor based on geometric means was 1.67.

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