SIDE EFFECTS

Of the patients treated with BEXTRA Tablets in controlled arthritis trials,2665 were patients with OA,and 2684 were patients with RA.More than 4000 patients have received a chronic total daily dose of BEXTRA 10 mg or more.More than 2800 patients have received BEXTRA 10 mg/day,or more,for at least 6 months and 988 of these have received BEXTRA for at least 1 year.

Osteoarthritis and Rheumatoid Arthritis

Table 4 lists all adverse events,regardless of causality,that occurred in ³ 2.0% of patients receiving BEXTRA 10 and 20mg/day in studies of three months or longer from 7 controlled studies conducted in patients with OA or RA that included a placebo and/or a positive control group.

In these placebo- and active-controlled clinical trials, the discontinuation rate due to adverse events was 7.5% for arthritis patients receiving valdecoxib 10 mg daily, 7.9% for arthritis patients receiving valdecoxib 20 mg daily and 6.0% for patients receiving placebo.

In the seven controlled OA and RA studies, the following adverse events occurred in 0.1–1.9% of patients treated with BEXTRA 10 –20 mg daily, regardless of causality.

Application site disorders: Cellulitis, dermatitis contact

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, vagi-nal hemorrhage

Gastrointestinal: Abnormal stools, constipation, diverticulosis, dry mouth, duodenal ulcer, duodenitis, eructation, esophagitis, fecal incontinence, gastric ulcer, gastritis, gastroenteritis, gastroe-sophageal reflux, hematemesis, hematochezia, hemorrhoids, hem-orrhoids 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

Table 4:Adverse Events with Incidence ³ 2.0% in Valdecoxib Treatment Groups: Controlled Arthritis Trials of Three Months or Longer
			(Total Daily Dose)
			Valdecoxib		Diclofenac	Ibuprofen	Naproxen
Adverse Event		Placebo	10 mg	20 mg	150 mg	2400 mg	1000 mg
Number Treated		973	1214	1358	711	207	766
Autonomic Nervous System Disorders
Hypertension		0.6	1.6	2.1	2.5	2.4	1.7
Body as a Whole
Backpain		1.6	1.6	2.7	2.8	1.4	1.0
Edema peripheral		0.7	2.4	3.0	3.2	2.9	2.1
Influenza-like symptoms		2.2	2.0	2.2	3.1	2.9	2.0
Injury accidental		2.8	4.0	3.7	3.9	3.9	3.0
Central and Peripheral Nervous System Disorders
Dizziness		2.1	2.6	2.7	4.2	3.4	2.7
Headache		7.1	4.8	8.5	6.6	4.3	5.5
Gastrointestinal System Disorders
Abdominal fullness		2.0	2.1	1.9	3.0	2.9	2.5
Abdominal pain		6.3	7.0	8.2	17.0	8.2	10.1
Diarrhea		4.2	5.4	6.0	10.8	3.9	4.7
Dyspepsia		6.3	7.9	8.7	13.4	15.0	12.9
Flatulence		4.1	2.9	3.5	3.1	7.7	5.4
Nausea		5.9	7.0	6.3	8.4	7.7	8.7
Musculoskeletal System Disorders
Myalgia		1.6	2.0	1.9	2.4	2.4	1.4
Respiratory System Disorders
Sinusitis		2.2	2.6	1.8	1.1	3.4	3.4
Upper respiratory tract infection		6.0	6.7	5.7	6.3	4.3	6.4
Skin and Appendages Disorders
Rash		1.0	1.4	2.1	1.5	0.5	1.4

, pneumonia, pharyngitis, pleurisy, rhinitis

Skin and appendages: Acne, alopecia, dermatitis, dermatitis fun-gal, eczema, photosensitivity allergic reaction, pruritus, rash ery-thematous, rash maculopapular, rash psoriaform, skin dry, skin hypertrophy, skin ulceration, sweating increased, urticaria

Special senses: Taste perversion


Urinary system: Albuminuria, cystitis, dysuria, hematuria, micturition frequency increased, pyuria, urinary incontinence, urinary tract infection

Vascular: Claudication intermittent, hemangioma acquired, varicose vein

Vision: Blurred vision, cataract, conjunctival hemorrhage, con-junctivitis, eye pain, keratitis, vision abnormal

White cell and RES disorders: Eosinophilia, leukopenia, leukocytosis, lymphadenopathy, lymphangitis, lymphopenia

Postmarketing Experience :The following reactions have been identified during postmarketing use of BEXTRA.These reactions have been chosen for inclusion either due to their seriousness,reporting frequency,possible causal relationship to BEXTRA,or a combination of these factors.Because these reactions were reported voluntarily from a population of uncertain size,it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General:Hypersensitivity reactions (including anaphylactic reactions and angioedema) Skin and appendages:Erythema multiforme,exfoliative dermatitis,Stevens-Johnson syndrome,toxic epidermal necrolysis

Other serious adverse events that were reported rarely (estimated <0.1%) in clinical trials, regardless of causality, in patients taking BEXTRA:

Autonomic nervous system disorders: Hypertensive encephalop-athy, vasospasm

Cardiovascular: Abnormal ECG,aortic stenosis, atrial fibrillation, carotid stenosis, coronary thrombosis, heart block,heart valve disorders, mitral insufficiency, myocardial infarction, myocardial ischemia, pericarditis, syncope, thrombophlebitis, unstable angina, ventricular fibrillation

Central, peripheral nervous system: Convulsions

Endocrine: Hyperparathyroidism

Female reproductive: Cervical dysplasia

Gastrointestinal: Appendicitis, colitis with bleeding, dysphagia, esophageal perforation, gastrointestinal bleeding, ileus, intestinal obstruction, peritonitis

Hemic: Lymphoma-like disorder, pancytopenia

Liver and biliary system: Cholelithiasis

Metabolic: Dehydration

Musculoskeletal: Pathological fracture, osteomyelitis

Neoplasm: Benign brain neoplasm, bladder carcinoma, carcinoma, gastric carcinoma, prostate carcinoma, pulmonary carcinoma

Platelets (bleeding or clotting): Embolism, pulmonary embolism, thrombosis

Psychiatric: Manic reaction, psychosis

Renal: Acute renal failure

Resistance mechanism disorders: Sepsis

Respiratory: Apnea, pleural effusion, pulmonary edema, pulmonary fibrosis, pulmonary infarction, pulmonary hemorrhage, respiratory insufficiency

Skin: Basal cell carcinoma, malignant melanoma

Urinary system: Pyelonephritis, renal calculus

Vision: Retinal detachment


DRUG INTERACTIONS

The drug interaction studies with valdecoxib were performed both with valdecoxib and a rapidly hydrolyzed intravenous prodrug form. The results from trials using the intravenous prodrug are reported in this section as they relate to the role of valdecoxib in drug interactions.

General: In humans,valdecoxib metabolism is predominantly mediated via CYP 3A4 and 2C9 with glucuronidation being a further (20%) route of metabolism.In vitrostudies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 (IC50 = 6 µg/mL),and a weak inhibitor of both 3A4 (IC50 = 44µg/mL) and 2C9 (IC50 = 13 µg/mL).In view of the limitations of in vitrostudies and the high valdecoxib IC50 values,the potential for such metabolic inhibitory effects in vivoat therapeutic doses of valdecoxib is low.

Aspirin: Concomitant administration of aspirin with valdecoxib may result in an increased risk of GI ulceration and complications compared to valdecoxib alone.Because of its lack of anti-platelet effect valdecoxib is not a substitute for aspirin for cardiovascular prophylaxis.

In a parallel group drug interaction study comparing the intravenous prodrug form of valdecoxib at 40 mg BID (n=10) vs placebo (n=9),valdecoxib had no effect on in vitroaspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation.

Methotrexate: Valdecoxib 10 mg BID did not show a significant effect on the plasma exposure or renal clearance of methotrexate.

ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors.This interaction should be given consideration in patients taking BEXTRA concomitantly with ACE-inhibitors.

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.

Anticonvulsants: Anticonvulsant drug interaction studies with val-decoxib have not been conducted.As with other drugs,routine monitoring should be performed when therapy with BEXTRA is either initiated or discontinued in patients on anticonvulsant therapy.

Dextromethorphan: Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4.Coadministration with val-decoxib (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that,at these doses,val-decoxib is a weak inhibitor of 2D6.Dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers.

Lithium: Valdecoxib 40 mg BID for 7 days produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium.Lithium carbonate (450mg BID for 7 days) had no effect on valdecoxib pharmacokinetics.

Warfarin: The effect of valdecoxib on the anticoagulant effect of warfarin (1 – 8 mg/day) was studied in healthy subjects by coadminis-tration of BEXTRA 40 mg BID for 7 days.Valdecoxib caused a statistically significant increase in plasma exposures of R-warfarin and S-warfarin (12% and 15%,respectively),and in the pharmacodynamic effects (prothrombin time,measured as INR) of warfarin.While mean INR values were only slightly increased with coadministration of valdecoxib,the day-to-day variability in individual INR values was increased.Anticoagulant therapy should be monitored,particularly during the first few weeks,after initiating therapy with BEXTRA in patients receiving warfarin or similar agents.

Fluconazole and Ketoconazole: Ketoconazole and fluconazole are predominantly CYP 3A4 and 2C9 inhibitors, respectively. Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced a significant increase in exposure of valdecoxib.Plasma exposure (AUC) to valdecoxib was increased 62% when coadministered with flucona-zole and 38% when coadministered with ketoconazole.

Glyburide: Glyburide is a CYP 3A4 substrate.Coadministration of valdecoxib (10 mg BID for 7 days) with glyburide (5 mg QD or 10 mg BID) did not affect the pharmacokinetics (exposure) of glyburide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Valdecoxib was not carcinogenic in rats given oral doses up to 7.5mg/kg/day for males and 1.5mg/kg/day for females (equivalent to approximately 2- to 6-fold human exposure at 20 mg QD as measured by the AUC(0-24hr)) or in mice given oral doses up to 25mg/kg/day for males and 50mg/kg/day for females (equivalent to approximately 0.6- to 2.4-fold human exposure at 20 mg QD as measured by the AUC(0-24hr)) for two years..

Valdecoxib was not mutagenic in an Ames test or a mutation assay in Chinese hamster ovary (CHO) cells,nor was it clastogenic in a chromosome aberration assay in CHO cells or in an in vivomicronucleus test in rat bone marrow.

Valdecoxib did not impair male rat fertility at oral doses up to 9.0mg/kg/day (equivalent to approximately 3- to 6-fold human exposure at 20 mg QD as measured by the AUC (0-24hr)).In female rats,a decrease in ovulation with increased pre- and post-implantation loss resulted in decreased live embryos/fetuses at doses ³ 2 mg/kg/day (equivalent to approximately 2-fold human exposure at 20mg QD as measured by the AUC (0-24hr) for valdecoxib).The effects on female fertility were reversible.This effect is expected with inhibition of prostaglandin synthesis and is not the result of irreversible alteration of female reproductive function.

Pregnancy

Teratogenic Effects: Pregnancy Category C.

The incidence of fetuses with skeletal anomalies such as semi-bipartite thoracic vertebra centra and fused sternebrae was slightly higher in rabbits at an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposures at 20mg QD as measured by the AUC(0-24hr)) throughout organogenesis.Valdecoxib was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day (equivalent to approximately 8-fold human exposures at 20 mg QD as measured by the AUC(0-24hr)).

Valdecoxib was not teratogenic in rats up to an oral dose of 10mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC (0-24hr)).There are no studies in pregnant women.However,valdecoxib crosses the placenta in rats and rabbits.BEXTRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic Effects: Valdecoxib caused increased pre-and post-implantation loss with reduced live fetuses at oral doses

³ 10mg/kg/day (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC (0-24hr)) in rats and an oral dose of 40 mg/kg/day (equivalent to approximately 72-fold human exposure at 20 mg QD as measured by the AUC (0-24hr)) in rabbits throughout organogenesis.In addition,reduced neonatal survival and decreased neonatal body weight when rats were treated with valdecoxib at oral doses ³ 6 mg/kg/day (equivalent to approximately 7-fold human exposure at 20 mg QD as measured by the AUC(0-24hr)) throughout organogenesis and lactation period.No studies have been conducted to evaluate the effect of valdecoxib on the closure of the ductus arteriosus in humans.Therefore,as with other drugs known to inhibit prostaglandin synthesis,use of BEXTRA during the third trimester of pregnancy should be avoided.

Labor and Delivery

Valdecoxib produced no evidence of delayed labor or parturition at oral doses up to 10 mg/kg/day in rats (equivalent to approximately 19-fold human exposure at 20 mg QD as measured by the AUC (0-24hr)). The effects of BEXTRA on labor and delivery in pregnant women are unknown.

Nursing Mothers

Valdecoxib and its active metabolite are excreted in the milk of lactating rats.It is not known whether this drug is excreted in human milk.Because many drugs are excreted in human milk,and because of the potential for adverse reactions in nursing infants from BEXTRA,a decision should be made whether to discontinue nursing or to discontinue the drug,taking into account the importance of the drug to the mother and the importance of nursing to the infant.

Pediatric Use

Safety and effectiveness of BEXTRA in pediatric patients below the age of 18 years have not been evaluated.

Geriatric Use

Of the patients who received BEXTRA in arthritis clinical trials of three months duration,or greater,approximately 2100 were 65 years of age or older,including 570 patients who were 75 years or older.No overall differences in effectiveness were observed between these patients and younger patients.