Mechanism of Action

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. Studies to elucidate the mechanism of action of VIOXX in the acute treatment of migraine have not been conducted.

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 (C_max) following a single 25-mg dose were 3286 (±843) nghr/mL and 207 (±111) ng/mL, respectively. Both C_max 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 C_max 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 (T_max), as assessed in nine pharmacokinetic studies, is 2 to 3 hours. Individual T_max values in these studies ranged between 2 to 9 hours. This may not reflect rate of absorption as T_max may occur as a secondary peak in some individuals. With multiple dosing, steady-state conditions are reached by Day 4. The AUC_0-24hr and C_max at steady state after multiple doses of 25 mg rofecoxib was 4018 (±1140) nghr/mL and 321 (±104) ng/mL, respectively, in healthy adults. The accumulation factor based on geometric means was 1.67. The AUC_0-24hr and C_max at steady state after multiple doses of 25 mg rofecoxib was 6934 (±2158) nghr/mL and 519 (±163) ng/mL, respectively, in adult RA patients (N=12, mean body weight 62 kg).

VIOXX Tablets 12.5 mg and 25 mg are bioequivalent to VIOXX Oral Suspension 12.5 mg/5 mL and 25 mg/5 mL, respectively.

Food had no significant effect on either the peak plasma concentration (C_max) or extent of absorption (AUC) of rofecoxib when VIOXX Tablets were taken with a high fat meal. The time to peak plasma concentration (T_max), however, was delayed by 1 to 2 hours. The food effect on the suspension formulation has not been studied. VIOXX tablets can be administered without regard to timing of meals.

There was a 13% and 8% decrease in AUC when VIOXX was administered with calcium carbonate antacid and magnesium/aluminum antacid to elderly subjects, respectively. There was an approximate 20% decrease in C_max of rofecoxib with either antacid.

Rofecoxib is approximately 87% bound to human plasma protein over the range of concentrations of 0.05 to 25 mcg/mL. The apparent volume of distribution at steady state (V_dss) is approximately 91 L following a 12.5-mg dose and 86 L following a 25-mg dose.

Rofecoxib has been shown to cross the placenta in rats and rabbits, and the blood-brain barrier in rats.

Brand Name: Vioxx
Generic Name: Rofecoxib

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