The FDA announced on November 15, 2002, that it had received about 20 reports of serious reactions from Bextra. Pharmacia had issued a "Dear Healthcare Professional" letter two days earlier. Previously, on October 22, the European Medicines Evaluation Agency (the European counterpart to the FDA) issued a public statement warning of skin related side effects. More recently, in light of the growing evidence of serious cardiac risks associated with Cox-2 inhibitors generally, --- and most notoriously the now recalled pain medication Vioxx-- the medical community has become increasingly concerned with the increased risk of heart attack and stroke posed by Bextra use.:

The Problem With Cox-2 Inhibitors:

The family of COX-2 inhibitor drugs to which Bextra belongs seem to be associated with a new group of side effects involving the circulatory system. In the most recent research on the question, the Cleveland Clinic Heart Center analyzed the data from four prior trials of another Cox-2 drug—Vioxx-- and a similar drug called Celebrex involving 18,064 patients. These studies were used by the drugmakers to gain FDA approval of the medications. The Cleveland Clinic's analysis revealed that all four studies showed a trend toward an increase in heart attacks or blood clotting events, such as stroke, venous thrombophlebitis and pulmonary embolism. The clinic also revealed that through October 2000, approximately 200 major clotting events occurred in patients receiving at least one of these two drugs, with more than 50 of these events classified as heart attacks, according to FDA reports. The clinic's findings were published on August 22, 2001, in the Journal of the American Medical Association.

Other recent clinical studies demonstrate that Cox-2 inhibitor drugs raise blood pressure, which may contribute to a tendency toward increased heart attack risk.

One study has demonstrated that Cox-2 inhibitors inhibit prostacylin formation in the cells lining blood vessels. Prostacylin is a naturally occurring substance that tends to dilate blood vessels and prevent clotting. The study, which was published in the August 14, 2001, issue of the medical journal Circulation, concludes that its results "raise concerns regarding an increased risk of acute vascular events in patients receiving COX-2 inhibitors."

Another study, published in the August 29, 2000 issue of the journal Proceedings of the National Academy of Sciences, concluded that COX-2 has a "cardioprotective" effect. This suggests that blocking COX-2 may increase the risk of heart disease.

Possible Side Effects of Bextra

The following side effects may be linked to Bextra use:

Cardiovascular: Aggravated hypertension, aneurysm, anginapectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disorder, heart murmur, hypotension.

Central, peripheral nervous system: Cerebrovascular disorder, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, pares-thesia, tremor, twitching, vertigo.

Endocrine: Goiter.

Female reproductive: Amenorrhea, dysmenorrhea, leukorrhea, mastitis, menstrual disorder, menorrhagia, menstrual bloating, vaginal hemorrhage.

Gastrointestinal: Abnormal stools, constipation, diverticulosis, dry mouth, duodenal ulcer, duodenitis, eructation, esophagitis, fecal incontinence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux, hematemesis, hematochezia, hemorrhoids, hemorrhoids bleeding, hiatal hernia, melena, stomatitis, stool frequency increased, tenesmus, tooth disorder, vomiting.

General: Allergy aggravated, allergic reaction, asthenia, chest pain, chills, cyst NOS, edema generalized, face edema, fatigue, fever, hot flushes, halitosis, malaise, pain, periorbital swelling, peripheral pain Hearing and vestibular: Ear abnormality, earache, tinnitus.

Heart rate and rhythm: Bradycardia, palpitation, tachycardia.

Hemic: Anemia
Liver and biliary system: Hepatic function abnormal, hepatitis, ALT increased, AST increased.

Male reproductive: Impotence, prostatic disorder.

Metabolic and nutritional: Alkaline phosphatase increased, BUN increased, CPK increased, creatinine increased, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypocalcemia, hypokalemia, LDH increased, thirst increased, weight decrease, weight increase, xerophthalmia.

Musculoskeletal: Arthralgia, fracture accidental, neck stiffness, osteoporosis, synovitis, tendonitis.

Neoplasm: Breast neoplasm, lipoma, malignant ovarian cyst.

Platelets (bleeding or clotting): Ecchymosis, epistaxis, hematoma NOS, thrombocytopenia.

Psychiatric: Anorexia, anxiety, appetite increased, confusion, depression, depression aggravated, insomnia, nervousness, morbid dreaming, somnolence.

Resistance mechanism disorders: Herpes simplex, herpes zoster, infection fungal,infection soft tissue, infection viral, moniliasis, moniliasis genital, otitis media.

Respiratory: Abnormal breath sounds, bronchitis, bronchospasm, coughing, dyspnea, emphysema, laryngitis.

Skin Related Side Effects

The skin diseases associated with Bextra use are:

1. Erythema multiforme, which is an acute mucocutaneous hypersensitivity reaction of variable severity characterized by a symmetrically distributed skin eruption, with or without mucous membrane lesions.

2. Exfoliative dermatitis, which involves a scaling erythematous dermatitis involving 90% or more of the cutaneous surface.

3. Stevens-Johnson syndrome (SJS), which is an immune-complex-mediated hypersensitivity complex that is a severe expression of erythema multiforme. SJS typically involves the skin and the mucous membranes. While minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness. SJS is a serious systemic disorder with the potential for severe morbidity and even death.

4. Toxic epidermal necrolysis, which is a severe mucocutaneous exfoliative disease with an uncertain pathogenesis and a high mortality rate.

Hypersensitivity Reactions

The hypersensitivity reactions associated with Bextra use are:

1. Anaphylaxis, which is a severe allergic reaction that occurs rapidly and causes a life-threatening response involving the whole body. It is potentially fatal.

2. Angioedema, which is swelling that occurs in the tissue just below the surface of the skin. Complications range from dysphonia or dysphagia to respiratory distress, complete airway obstruction, and death.