Brands, Medical Use, Clinical Data
Drug Category
- Anti-Inflammatory Agents, Non-Steroidal
- Cyclooxygenase Inhibitors
Dosage Forms
- Tablet (12.5 mg, 25 mg, or 50 mg)
- Oral suspension (12.5 or 25 mg per 5 mL solution)
Brands / Synonyms
MK 966; MK 996
; Vioxx
Indications
For the treatment of osteoarthritis, acute pain in adults and menstrual pain.
Pharmacology
Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Rofecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, rofecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism.
Mechanism of Action
Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Rofecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, rofecoxib does not inhibit platelet aggregation.
Absorption
The mean oral bioavailability of rofecoxib at therapeutically recommended doses of 12.5, 25, and 50 mg is approximately 93%.
Toxicity
No overdoses of rofecoxib were reported during clinical trials. Administration of single doses of rofecoxib 1000 mg to 6 healthy volunteers and multiple doses of 250 mg/day for 14 days to 75 healthy volunteers did not result in serious toxicity.
Biotrnasformation / Drug Metabolism
Hepatic. Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-dihydro derivatives of rofecoxib, which account for nearly 56% of recovered radioactivity in the urine. An additional 8.8% of the dose was recovered as the glucuronide of the hydroxy derivative, a product of oxidative metabolism. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (< 5%). These metabolites are inactive as COX-1 or COX-2 inhibitors. Cytochrome P450 plays a minor role in metabolism of rofecoxib.
Contraindications
VIOXX is contraindicated in patients with known hypersensitivity to rofecoxib or any other component
of VIOXX.
VIOXX should not be given to patients who have experienced asthma, urticaria, or allergic-type
reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been
reported in such patients.
Drug Interactions
ACE inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of
Angiotensin Converting Enzyme (ACE) inhibitors. In patients with mild to moderate hypertension, administration of 25
mg daily of VIOXX with the ACE inhibitor benazepril, 10 to 40 mg for 4 weeks, was associated with an average increase
in mean arterial pressure of about 3 mm Hg compared to ACE inhibitor alone. This interaction should be given
consideration in patients taking VIOXX concomitantly with ACE inhibitors.
Aspirin
Concomitant administration of low-dose aspirin with VIOXX may result in an increased rate of GI
ulceration or other complications, compared to use of VIOXX alone. In a 12-week endoscopy study conducted in OA
patients there was no difference in the cumulative incidence of endoscopic gastroduodenal ulcers in patients taking
low-dose (81 mg) enteric coated aspirin plus VIOXX 25 mg daily, as compared to those taking ibuprofen 2400 mg daily
alone. Patients taking low-dose aspirin plus ibuprofen were not studied.
At steady state, VIOXX 50 mg once daily had no effect on the anti-platelet activity of low-dose (81 mg
once daily) aspirin, as assessed by ex vivo platelet aggregation and serum TXB2 generation in clotting blood.
Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis.
Therefore, in patients taking VIOXX, antiplatelet therapies should not be discontinued and should be considered in
patients with an indication for cardiovascular prophylaxis. Prospective, long-term studies on concomitant
administration of VIOXX and aspirin have not been conducted.
Cimetidine
Co-administration with high doses of cimetidine [800 mg twice daily] increased the Cmax of
rofecoxib by 21%, the AUC0-120hr by 23% and the t1/2 by 15%. These small changes are not
clinically significant and no dose adjustment is necessary.
Digoxin
Rofecoxib 75 mg once daily for 11 days does not alter the plasma concentration profile or renal
elimination of digoxin after a single 0.5 mg oral dose.
Furosemide
Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the
natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of
renal prostaglandin synthesis.
Ketoconazole
Ketoconazole 400 mg daily did not have any clinically important effect on the pharmacokinetics of
rofecoxib.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.
In post-marketing experience there have been reports of increases in plasma lithium levels. Thus, when VIOXX and
lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
VIOXX 12.5, 25, and 50 mg, each dose administered once daily for 7 days, had no effect
on the plasma concentration of methotrexate as measured by AUC0-24hr in patients receiving
single weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. At higher than recommended doses, VIOXX 75
mg administered once daily for 10 days increased plasma concentrations by 23% as measured by AUC0-24hr in
patients receiving methotrexate 7.5 to 15 mg/week for rheumatoid arthritis. At 24 hours postdose, a similar
proportion of patients treated with methotrexate alone (94%) and subsequently treated with methotrexate
co-administered with 75 mg of rofecoxib (88%) had methotrexate plasma concentrations below the measurable limit (5
ng/mL). Standard monitoring of methotrexate-related toxicity should be continued if VIOXX and methotrexate are
administered concomitantly.
Oral Contraceptives
Rofecoxib did not have any clinically important effect on the pharmacokinetics of ethinyl estradiol
and norethindrone.
Prednisone/prednisolone
Rofecoxib did not have any clinically important effect on the pharmacokinetics of prednisolone or
prednisone.
Rifampin
Co-administration of VIOXX with rifampin 600 mg daily, a potent inducer of hepatic metabolism,
produced an approximate 50% decrease in rofecoxib plasma concentrations. Therefore, a starting daily dose of 25 mg of
VIOXX should be considered for the treatment of osteoarthritis when VIOXX is co-administered with potent inducers of
hepatic metabolism.
Theophylline
VIOXX 12.5, 25, and 50 mg administered once daily for 7 days increased plasma theophylline
concentrations (AUC(0-¥)) by 38 to 60% in healthy subjects administered a
single 300-mg dose of theophylline. Adequate monitoring of theophylline plasma concentrations should be considered
when therapy with VIOXX is initiated or changed in patients receiving theophylline. These data suggest that rofecoxib
may produce a modest inhibition of cytochrome P450 (CYP) 1A2. Therefore, there is a potential for an interaction with
other drugs that are metabolized by CYP 1A2 (e.g., amitriptyline, tacrine, and zileuton).
Warfarin
Anticoagulant activity should be monitored, particularly in the first few days after initiating or
changing VIOXX therapy in patients receiving warfarin or similar agents, since these patients are at an increased
risk of bleeding complications. In single and multiple dose studies in healthy subjects receiving both warfarin and
rofecoxib, prothrombin time (measured as INR) was increased by approximately 8% to 11%. In post-marketing experience,
bleeding events have been reported, predominantly in the elderly, in association with increases in prothrombin time
in patients receiving VIOXX concurrently with warfarin.
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