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Celecoxib is a fluoronated benzenesulfonamide derivative (C₁₇H₁₄F₃N₃O₂S; molecular wt = 381.38). It is a nonsteroidal anti-inflammatory drug (NSAID) with a highly selective cyclooxygenase-2 (COX-2) inhibitory action. It possesses anti-inflammatory, analgesic, and antipyretic activities. These actions are thought to be due to the inhibition of prostaglandin synthesis catalyzed by COX-2.

Celecoxib is indicated for the:

1. relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis in adult patients.
2. management of acute pain in adults.
3. treatment of primary dysmenorrhea.
4. management of familial adenomatous polyposis (FAP); to reduce the number of adenomatous colorectal polyps.

Pharmacokinetics

• Oral bioavailability has not been determined; peak plasma concentration (Cmax) occurs 3 hrs after dose ingestion. Food delays absorption by 1-2 hrs but it augments the extent of absorption by 10-20%.
• Coadministration with Mg⁺⁺ or Al⁺⁺ containing antacids reduces the Cmax by about 40% and absorption by 10%.
• Steady state level is reached after 5 days of treatment.
• Celecoxib is highly bound to plasma proteins (mainly albumin, but also to a₁ -acid glycoprotein. Its Vd (400 L) suggests wide tissue distribution.
• Compared to young subjects, elderly patients (> 65 yrs) showed a 50% increase in bioavailability (AUC) and a 40% increase in Cmax. Blacks showed a 40% increase in AUC compared to caucasians.
• Moderate liver disease increases celecoxib AUC by 180%, suggesting the need to reduce the dose in these patients
• Chronic renal insufficiency (GFR 35-60 mL/min) is associated with a lower AUC, but this not clinically significant change in kinetics.
• Animal studies showed that rofecoxib is able to cross the placenta and the blood-brain barrier.
• Celecoxib is metabolized to inactive metabolites by the cytochrome P450 2C9. These metabolites are excreted in the feces and to some extent in the urine. The lagest fraction of a celebrex dose is excreted in feces. The elimination half-life is highly variable due to a prolonged absorption process which is in turn due to the low water solubility of celecoxib. The socalled effective half-life is around 11 hrs.
• The use of celecoxib in advanced renal disease is not recommended at present because of the lack of safety information.
• Celecoxib is excreted in the milk of lactating animals and was found to be harmful to nursing infants. It is not known whether the same occurs in humans. However, it is use in lactating mothers is not recommended at the present.

Contraindications and Warnings

• Celecoxib is not indicated for Patients with proven hypersensitivity to sulfonamides, aspirin, or other NSAIDs.
• Celecoxib 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
• Patients at risk for GI bleeding should be monitored very closely when treated with NSAIDs.

Available As

• Oral capsules (100-mg and 200-mg)

Dose and Administration

• Osteoarthritis (OA): The recommended starting dose is 100 mg twice daily or 200 mg once daily.
• Rheumatoid Arthritis (RA): 100 or 200 mg twice daily.
• The drug may be taken with or without food.

Main Side Effects

• Warning: "NSAIDs should be prescribed with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients..."
• Celecoxib "should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs"
• Celecoxib should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.

Drug Interactions

• Concomitant administration of low-dose aspirin with celecoxib may result in an increased rate of GI ulceration or other complications, compared to use of celecoxib alone.
• Celecoxib is metabolized mainly by Cytochrome P450 2C9 and it is an inhibitor of the 2D6 isoform. Therefore, co-adminstration with drugs that are either inhibitors of 2C9 or substrates of 2D6 may result in a significant drug-drug interaction.
• Rifampin may Þ ñ celecoxib metabolism Þ ò rofecoxib level. This potential interaction has not yet been reported in clinical practice.
• Fluconazole Þ ò celecoxib metabolism Þ ñ celecoxib level.
• Celecoxib may inhibit warfarin metabolism and enhance its anticoagulant effect (ñ INR, particularly in the elderly)
• NSAIDs Þ ò natriuretic effect of furosemide and thiazide diuretics.
• As an NSAIDs, celecoxib Þ ò renal clearance of Li⁺ Þ ñ Li⁺ level. Thus, when celecoxib and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
• Celecoxib Þ ò Antihypertensive effect of ACE inhibitors.

References

1. Celebrex PI
2. Tive L. Celecoxib clinical profile. Rheumatology (Oxford). 2000;39 Suppl 2:21-8.
3. Mukherjee D et al. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8):954-9.
4. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345(6):433-42.
5. Brook RD et al. Nonsteroidal Anti-Inflammatory Drugs and Hypertension. J Clin Hypertens (Greenwich) 2000;(5):319-323.
6. Matheson AJ, Figgitt DP. Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs. 2001;61(6):833-65.
7. Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs. Am J Med. 2001;111(1):64-7