Special Alerts:

Celecoxib: FDA and Health Canada Actions - December 24, 2004

The Food and Drug Administration (FDA) has issued a Public Health Advisory regarding COX-2 inhibitors. Health Canada has issued a similar warning. Physicians are encouraged to carefully evaluate individual cardiovascular risk profiles prior to prescribing COX-2 inhibitors. The statement emphasizes that COX-2 inhibitors may be appropriate for patients who do not tolerate nonselective NSAIDs, those who are not doing well on NSAIDs, or in those with a history of gastrointestinal bleeding. However, due to safety concerns, COX-2 inhibitors may not be appropriate in patients with cardiovascular disease or in patients with significant risk factors for cardiovascular disease.

The market authorization (Notice of Compliance with Conditions) issued by Health Canada for the use of celecoxib to reduce the number of adenomatous colorectal polyps in patients with Familial Adenomatous Polyposis (FAP) has been suspended due to safety concerns. The manufacturer (Pfizer) has asked physicians to immediately contact all patients currently using celecoxib for FAP in order to advise them to discontinue the medication immediately.

Additional information is available at:

http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01336.html, last accessed December 28, 2004.

http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_69_e.html, last accessed December 28, 2004.

Celebrex®: Cardiovascular Risk Reported - December 17, 2004

Pfizer, Inc, the manufacturer of Celebrex® (celecoxib) has reported an increased risk of cardiovascular events in one clinical trial during an interim analysis. The increased risk was observed in a trial evaluating celecoxib in patients at risk of colon cancer, prompting the National Cancer Institute to end the study. Other similar clinical studies (which were subjected to analysis by data monitoring committees) are continuing, since an interim analysis of these trials did not reveal an increased risk of cardiovascular events. Further analysis of risk factors related to cardiovascular risk appear warranted. A notice posted by the Food and Drug Administration (FDA) states that the agency "will obtain all available data on these and other ongoing Celebrex® trials as soon as possible and will determine the appropriate regulatory action."

The FDA further notes that these new findings for celecoxib are similar to results with other drugs in this class. Increased cardiovascular risk noted in a study of rofecoxib (Vioxx®) led to a voluntary withdrawal of the product by Merck. In addition, another drug in this class, valdecoxib (Bextra®) demonstrated an increased risk for cardiovascular events in patients following cardiovascular surgery.

In their statement, the FDA encourages physicians to consider this developing information in risk to benefit evaluations as they consider the use of celecoxib in individual patients. In addition, the FDA advises an evaluation of alternative therapy. If physicians determine that continued use is appropriate for individual patients, the lowest effective dose of celecoxib should be prescribed. Pfizer has not announced a decision to withdraw celecoxib from the market as of December 20, 2004.

Additional information is available at http://www.fda.gov/bbs/topics/news/2004/new01144.html, last accessed December 20, 2004.

Pronunciation:

(se le KOKS ib)

U.S. Brand Names:

Generic Available:

Canadian Brand Names:

Use:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Anaphylactoid reactions may occur, even with no prior exposure to celecoxib. Use caution in patients with known or suspected deficiency of cytochrome P450 isoenzyme 2C9. Safety and efficacy have not been established in patients <18 years of age.

Adverse Reactions:

>10%: Central nervous system: Headache (16%)

2% to 10%:

Cardiovascular: Peripheral edema (2%)

Central nervous system: Insomnia (2%), dizziness (2%)

Dermatologic: Skin rash (2%)

Gastrointestinal: Dyspepsia (9%), diarrhea (6%), abdominal pain (4%), nausea (4%), flatulence (2%)

Neuromuscular & skeletal: Back pain (3%)

Respiratory: Upper respiratory tract infection (8%), sinusitis (5%), pharyngitis (2%), rhinitis (2%)

Miscellaneous: Accidental injury (3%)

0.1% to 2%:

Cardiovascular: Hypertension (aggravated), chest pain, MI, palpitation, tachycardia, facial edema

Central nervous system: Migraine, vertigo, hypoesthesia, fatigue, fever, pain, hypotonia, anxiety, depression, nervousness, somnolence

Dermatologic: Alopecia, dermatitis, photosensitivity, pruritus, rash (maculopapular), rash (erythematous), dry skin, urticaria

Endocrine & metabolic: Hot flashes, diabetes mellitus, hyperglycemia, hypercholesterolemia, breast pain, dysmenorrhea, menstrual disturbances, hypokalemia

Gastrointestinal: Constipation, tenesmus, diverticulitis, eructation, esophagitis, gastroenteritis, vomiting, gastroesophageal reflux, hemorrhoids, hiatal hernia, melena, stomatitis, anorexia, increased appetite, taste disturbance, dry mouth, tooth disorder, weight gain

Genitourinary: Prostate disorder, vaginal bleeding, vaginitis, monilial vaginitis, dysuria, cystitis, urinary frequency, incontinence, urinary tract infection,

Hematologic: Anemia, thrombocytopenia, ecchymosis

Hepatic: Alkaline phosphatase increased, transaminases increased

Neuromuscular & skeletal: Leg cramps, increased CPK, neck stiffness, arthralgia, myalgia, bone disorder, fracture, synovitis, tendonitis, neuralgia, paresthesia, neuropathy, weakness

Ocular: Glaucoma, blurred vision, cataract, conjunctivitis, eye pain

Otic: Deafness, tinnitus, earache, otitis media

Renal: Increased BUN, increased creatinine, albuminuria, hematuria, renal calculi

Respiratory: Bronchitis, bronchospasm, cough, dyspnea, laryngitis, pneumonia, epistaxis

Miscellaneous: Allergic reactions, diaphoresis increased, flu-like syndrome, breast cancer, herpes infection, bacterial infection, moniliasis, viral infection

<0.1% (Limited to important or life-threatening): CHF, ventricular fibrillation, pulmonary embolism, syncope, cerebrovascular accident, gangrene, thrombophlebitis, ataxia, acute renal failure, intestinal obstruction, pancreatitis, intestinal perforation, gastrointestinal bleeding, colitis, esophageal perforation, sepsis, sudden death

Postmarketing and/or case reports: Agranulocytosis, anaphylactoid reactions, angioedema, aplastic anemia, aseptic meningitis, erythema multiforme, exfoliative dermatitis, hepatic failure, hepatitis, hypoglycemia, hyponatremia, interstitial nephritis, intracranial hemorrhage (fatal in association with warfarin), jaundice, leukopenia, pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis

Overdosage/Toxicology:

Drug Interactions:

ACE inhibitors: Antihypertensive effect may be diminished by celecoxib.

Aspirin: Low-dose aspirin may be used with celecoxib, however, monitor for GI complications.

Fluconazole: Fluconazole increases celecoxib concentrations twofold. Lowest dose of celecoxib should be used.

Lithium: Plasma levels of lithium are increased by ~17% when used with celecoxib. Monitor lithium levels closely when treatment with celecoxib is started or withdrawn.

Loop diuretics (bumetanide, furosemide, torsemide): Natriuretic effect of furosemide and other loop diuretics may be decreased by celecoxib.

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Selective COX-2 inhibitors appear to have a lower risk of this toxicity, however, caution is warranted.

Thiazide diuretics: Natriuretic effects of thiazide diuretics may be decreased by celecoxib.

Warfarin: Bleeding events (including rare intracranial hemorrhage in association with increased prothrombin time) have been reported with concomitant use. Monitor closely, especially in the elderly.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (increased GI irritation).

Food: Peak concentrations are delayed and AUC is increased by 10% to 20% when taken with a high-fat meal.

Stability:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Distribution: Vd (apparent): 400 L

Protein binding: 97% to albumin

Metabolism: Hepatic via CYP2C9; forms inactive metabolites

Bioavailability: Absolute: Unknown

Half-life elimination: 11 hours

Time to peak: 3 hours

Excretion: Urine (as metabolites, <3% as unchanged drug)

Dosage:

Acute pain or primary dysmenorrhea: Initial dose: 400 mg, followed by an additional 200 mg if needed on day 1; maintenance dose: 200 mg twice daily as needed

Familial adenomatous polyposis (FAP): 400 mg twice daily

Osteoarthritis: 200 mg/day as a single dose or in divided dose twice daily

Rheumatoid arthritis: 100-200 mg twice daily

Elderly: No specific adjustment is recommended. However, the AUC in elderly patients may be increased by 50% as compared to younger subjects. Use the lowest recommended dose in patients weighing <50 kg.

Dosing adjustment in renal impairment: No specific dosage adjustment is recommended; not recommended in patients with advanced renal disease

Dosing adjustment in hepatic impairment: Reduced dosage is recommended (AUC may be increased by 40% to 180%); decrease dose by 50% in patients with moderate hepatic impairment (Child-Pugh Class II)

Monitoring Parameters:

Dietary Considerations:

Patient Education:

Anesthesia and Critical Care Concerns/Other Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Dental Comment:

Cross-reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in aspirin-sensitive patients. The manufacturer suggests that celecoxib should not be administered to patients with this type of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

The manufacturer studied the effect of celecoxib on the anticoagulant effect of warfarin and found no alteration of anticoagulant effect, as determined by prothrombin time, in patients taking 2 mg to 5 mg daily. However, the manufacturer has issued a caution when using celecoxib with warfarin since those patients are at increased risk of bleeding complications.

A literature report suggested that the enzyme COX-2 (cyclo-oxygenase type 2) is a major source of systemic prostacyclin biosynthesis in humans. Prostacyclin is involved in blood vessel dilation and inhibition of blood clotting. In view of the fact that celecoxib inhibits the COX-2 enzyme, prostacyclin production could be suppressed. The resultant effects on hemostasis are unknown at this time.

Recent news reports have noted an association between selective COX-2 inhibitors and increased cardiovascular risk. This was prompted by publication of a meta-analysis entitled "Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors" in the August 22, 2001, edition of the Journal of the American Medical Association (JAMA), viewable at http://jama.ama-assn.org/issues/v286n8/rfull/jsc10193.html. The researchers reanalyzed four previously published trials, assessing cardiovascular events in patients receiving either celecoxib or rofecoxib. They found an association between the use of COX-2 inhibitors and cardiovascular events (including MI and ischemic stroke). The annualized MI rate was found to be significantly higher in patients receiving celecoxib or rofecoxib than in the control (placebo) group from a recent meta-analysis of primary prevention trials. Although cause and effect cannot be established (these trials were originally designed to assess GI effects, not cardiovascular ones), the authors believe the available data raise a cautionary flag concerning the risk of cardiovascular events with the use of COX-2 inhibitors. The manufacturers of these agents, as well as other healthcare professionals, dispute the methods and validity of the study's conclusions. To date, the FDA has not required any change in the labeling of these agents. Further study is required before any potential risk may be defined.

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Dosage Forms:

International Brand Names: