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Efficacy and Safety of COX-2 Inhibitors vs. NSAIDs



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Am Fam Physician. 2002 Feb 15;65(4):696-697.

Despite having no greater clinical efficacy in the treatment of arthritis than standard, non-selective, nonsteroidal anti-inflammatory drugs (NSAIDs), the selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib and rofecoxib) are being widely prescribed because of their decreased potential for adverse gastrointestinal effects. FitzGerald and Patrono present an in-depth review of the pharmacology and clinical effects of selective COX-2 inhibitors, including a discussion of a possibly increased incidence of cardiovascular and renal disease among patients using these agents.

The discussion begins with a pharmacologic review of the selective cyclooxygenase-2 inhibitors (inflammatory mediators), also known as the “coxibs” (see accompanying table). One would expect the type-2–specific coxib drugs to be equally effective in their anti-inflammatory potency and decreased gastric effects because of their in vitro selectivity, but this is not completely reflected in human trials. Some of the older NSAIDs (e.g., diclofenac) have a relative type-2 specificity, and there are also some theoretic adverse effects of COX-2 suppression (e.g., slower healing of gastric ulcers, increased late-phase inflammatory mediators).

Pharmacokinetics, Metabolism, and Drug Interactions of Rofecoxib and Celecoxib

Feature Rofecoxib Celecoxib

Oral bioavailability (%)

92 to 93

22 to 40

Effect of food

Minimal

None

Elimination half-life (hours)

10 to 17

Approximately 11

Interaction with cytochrome P450 inhibitors

No

Yes

Interaction with digoxin

No

Not tested

Interaction with warfarin

Causes 10% increase in INR

No

Interaction with antihypertensive drugs

Increases blood pressure

Increases blood pressure

Approved daily dosages:

For osteoarthritis

12.5 to 25 mg

100 to 200 mg

For rheumatoid arthritis

200 to 400 mg

For acute pain

Up to 50 mg


INR = International Normalized Ratio.

Adapted with permission from FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:437.

Pharmacokinetics, Metabolism, and Drug Interactions of Rofecoxib and Celecoxib

View Table

Pharmacokinetics, Metabolism, and Drug Interactions of Rofecoxib and Celecoxib

Feature Rofecoxib Celecoxib

Oral bioavailability (%)

92 to 93

22 to 40

Effect of food

Minimal

None

Elimination half-life (hours)

10 to 17

Approximately 11

Interaction with cytochrome P450 inhibitors

No

Yes

Interaction with digoxin

No

Not tested

Interaction with warfarin

Causes 10% increase in INR

No

Interaction with antihypertensive drugs

Increases blood pressure

Increases blood pressure

Approved daily dosages:

For osteoarthritis

12.5 to 25 mg

100 to 200 mg

For rheumatoid arthritis

200 to 400 mg

For acute pain

Up to 50 mg


INR = International Normalized Ratio.

Adapted with permission from FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:437.

A predisposition to thrombosis may be possible with the use of coxib agents because of changes in prostacyclin levels in the blood vessel wall. The Vioxx Gastrointestinal Outcomes Research trial, which compared rofecoxib with naproxen in patients with rheumatoid arthritis, also monitored cardiovascular outcomes. The combined rate of nonfatal myocardial infarction, nonfatal stroke, and death from a vascular event was significantly higher in the rofecoxib group than in the naproxen group; however, the absolute difference was small (0.8 percent versus 0.4 percent, respectively). The Celecoxib Long-Term Arthritis Safety Study trial, comparing celecoxib to ibuprofen and diclofenac, did not detect a significant difference in the incidence of major cardiovascular events.

Nonselective standard NSAIDs have been associated with adverse renal effects. By blocking the production of vasodilator prostaglandins, which are needed to maintain renal blood flow, especially in the presence of volume depletion, NSAIDs can exacerbate renal insufficiency. No large-scale studies that have examined the renal effects of coxib drugs are noted by the authors, but smaller trials have shown the occurrence of hypertension in about 1 percent of patients and peripheral edema in about 2 to 4 percent of patients.

The authors conclude that celecoxib and rofecoxib have fewer adverse gastrointestinal effects compared with nonselective NSAIDs but may be associated with small elevations in the risk of cardiovascular and adverse renal effects.

FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. August 9, 2001;345:433–42.



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