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BEXTRA®
valdecoxib tablets
Serious Skin Reactions
- Serious skin reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme) have been reported in patients receiving BEXTRA. Some of these reactions have resulted in death.
- Patients appear to be at higher risk for these events within the first 2 weeks of treatment, but these may occur at any time during treatment.
- The reported rate of these serious skin events appears to be greater for BEXTRA as compared to other COX-2 agents.
- BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
DESCRIPTION
Valdecoxib is chemically designated as 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide and is a diaryl substituted isoxazole. It has the following chemical structure:
The empirical formula for valdecoxib is C16H14N2O3S, and the molecular weight is 314.36. Valdecoxib is a white crystalline powder that is relatively insoluble in water (10 µg/mL) at 25°C and pH 7.0, soluble in methanol and ethanol, and freely soluble in organic solvents and alkaline (pH=12) aqueous solutions.
BEXTRA Tablets for oral administration contain either 10 mg or 20 mg of valdecoxib. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol, polysorbate 80, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in animal models. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2). At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1).
Pharmacokinetics
Special Populations
Drug Interactions
For quantitative information on the following drug interaction studies, see PRECAUTIONS — Drug Interactions.
CLINICAL STUDIES
The efficacy and clinical utility of BEXTRA Tablets have been demonstrated in osteoarthritis (OA), rheumatoid arthritis (RA) and in the treatment of primary dysmenorrhea.
Osteoarthritis
BEXTRA was evaluated for treatment of the signs and symptoms of osteoarthritis of the knee or hip, in five double-blind, randomized, controlled trials in which 3918 patients were treated for 3 to 6 months. BEXTRA was shown to be superior to placebo in improvement in three domains of OA symptoms: (1) the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness and functional measures in OA, (2) the overall patient assessment of pain, and (3) the overall patient global assessment. The two 3-month pivotal trials in OA generally showed changes statistically significantly different from placebo, and comparable to the naproxen control, in measures of these domains for the 10 mg/day dose. No additional benefit was seen with a valdecoxib 20-mg daily dose.
Rheumatoid Arthritis
BEXTRA demonstrated significant reduction compared to placebo in the signs and symptoms of RA, as measured by the ACR (American College of Rheumatology) 20 improvement, a composite defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five: patient global, physician global, patient pain, patient function assessment, and C-reactive protein (CRP). BEXTRA was evaluated for treatment of the signs and symptoms of rheumatoid arthritis in four double-blind, randomized, controlled studies in which 3444 patients were treated for 3 to 6 months. The two 3-month pivotal trials compared valdecoxib to naproxen and placebo. The results for the ACR20 responses in these trials are shown below (Table 2). Trials of BEXTRA in rheumatoid arthritis allowed concomitant use of corticosteroids and/or disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, gold salts, and hydroxychloroquine. No additional benefit was seen with a valdecoxib 20-mg daily dose.
| Study 1 | Study 2 | |
|---|---|---|
| BEXTRA 10 mg/day | 49% | 46% |
| BEXTRA 20 mg/day | 48% | 47% |
| Naproxen 500 mg BID | 44% | 53% |
| Placebo | 32% (70/222) | 32% (71/220) |
Primary Dysmenorrhea
BEXTRA was compared to naproxen sodium 550 mg in two placebo-controlled studies of women with moderate to severe primary dysmenorrhea. The onset of analgesia was within 60 minutes for BEXTRA 20 mg. The onset, magnitude, and duration of analgesic effect with BEXTRA 20 mg were comparable to naproxen sodium 550 mg.
Safety Studies
INDICATIONS AND USAGE
BEXTRA Tablets are indicated:
- For relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.
- For the treatment of primary dysmenorrhea.
CONTRAINDICATIONS
BEXTRA should not be given to patients who have demonstrated allergic-type reactions to sulfonamides.
BEXTRA Tablets are contraindicated in patients with known hypersensitivity to valdecoxib. BEXTRA should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs are possible in such patients (see WARNINGS — Anaphylactoid Reactions, and PRECAUTIONS — Preexisting Asthma).
BEXTRA is contraindicated for the treatment of post-operative pain immediately following coronary artery bypass graft (CABG) surgery and should not be used in this setting. (See CLINICAL STUDIES — Safety Studies).
WARNINGS
Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation
Serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine can occur at any time with or without warning symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor gastrointestinal problems such as dyspepsia are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation caused by NSAIDs appear to occur in approximately 1% of patients treated for 3 to 6 months and 2–4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
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 and therefore special care should be taken in treating this population. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold higher risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status. (See CLINICAL STUDIES — Safety Studies.)
Serious Skin Reactions
Valdecoxib contains a sulfonamide moiety and patients with a known history of a sulfonamide allergy may be at a greater risk of skin reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions.
Serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported through postmarketing surveillance in patients receiving BEXTRA (see ADVERSE REACTIONS — Postmarketing Experience). Fatalities due to Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Patients appear to be at higher risk for these events early in the course of therapy, with the onset of the event occurring in the majority of cases within the first two weeks of treatment. BEXTRA should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Serious skin reactions have been reported with other COX-2 inhibitors during postmarketing experience. The reported rate of these events appears to be greater for BEXTRA as compared to other COX-2 agents (see Boxed Warning — Serious Skin Reactions).
Anaphylactoid Reactions
In postmarketing experience, cases of hypersensitivity reactions (anaphylactic reactions and angioedema) have been reported in patients receiving BEXTRA (see ADVERSE REACTIONS — Postmarketing Experience). These cases have occurred in patients with and without a history of allergic-type reactions to sulfonamides (see CONTRAINDICATIONS). BEXTRA 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 (see CONTRAINDICATIONS and PRECAUTIONS — Preexisting Asthma).
Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Coronary Artery Bypass Graft Surgery
Patients treated with BEXTRA for pain following coronary artery bypass graft surgery have a higher risk for cardiovascular/thromboembolic events, deep surgical infections or sternal wound complications. BEXTRA is therefore contraindicated for the treatment of postoperative pain following CABG surgery. (See CONTRAINDICATIONS and CLINICAL STUDIES-Safety Studies).
Advanced Renal Disease
No information is available regarding the safe use of BEXTRA Tablets in patients with advanced kidney disease. Therefore, treatment with BEXTRA is not recommended in these patients. If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS — Renal Effects).
Pregnancy
In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General
BEXTRA Tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of valdecoxib in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. These laboratory abnormalities may progress, may remain unchanged, or may remain transient with continuing therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure (some with fatal outcome) have been reported with NSAIDs. In controlled clinical trials of valdecoxib, the incidence of borderline (defined as 1.2- to 3.0-fold) elevations of liver tests was 8.0% for valdecoxib and 8.4% for placebo, while approximately 0.3% of patients taking valdecoxib, and 0.2% of patients taking placebo, had notable (defined as greater than 3-fold) elevations of ALT or AST.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with BEXTRA. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), BEXTRA should be discontinued.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and Angiotensin Converting Enzyme (ACE) inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Caution should be used when initiating treatment with BEXTRA in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with BEXTRA. Caution is also recommended in patients with preexisting kidney disease. (See WARNINGS — Advanced Renal Disease.)
Hematological Effects
Anemia is sometimes seen in patients receiving BEXTRA. Patients on long-term treatment with BEXTRA should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
BEXTRA does not generally affect platelet counts, prothrombin time (PT), or activated partial thromboplastin time (APTT), and does not appear to inhibit platelet aggregation at indicated dosages (see CLINICAL STUDIES — Safety Studies — Platelets).
Fluid Retention and Edema
Fluid retention and edema have been observed in some patients taking BEXTRA (see ADVERSE REACTIONS). Therefore, BEXTRA should be used with caution in patients with fluid retention, hypertension, or heart failure.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, BEXTRA should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
BEXTRA can cause GI discomfort and, rarely, more serious GI side effects, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS — Gastrointestinal (GI) Effects — Risk of GI Ulceration, Bleeding, and Perforation).
Patients should report to their physicians, signs or symptoms of gastrointestinal ulceration or bleeding, weight gain, or edema.
Patients should be instructed to discontinue treatment and seek medical attention at the first signs of a skin reaction (pruritus, rash, erythema, or mucosal lesions) (see WARNINGS — Serious Skin Reactions).
Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS — Anaphylactoid Reactions).
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical attention.
In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Valdecoxib was not carcinogenic in rats given oral doses up to 7.5 mg/kg/day for males and 1.5 mg/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 25 mg/kg/day for males and 50 mg/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 vivo micronucleus test in rat bone marrow.
Valdecoxib did not impair male rat fertility at oral doses up to 9.0 mg/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 ≥2 mg/kg/day (equivalent to approximately 2-fold human exposure at 20 mg 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
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.
ADVERSE REACTIONS
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 uls all adverse events, regardless of causality, that occurred in ≥2.0% of patients receiving BEXTRA 10 and 20 mg/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.
| (Total Daily Dose) | ||||||
|---|---|---|---|---|---|---|
| Valdecoxib | Diclofenac | Ibuprofen | Naproxen | |||
| Adverse Event Number Treated | Placebo 973 | 10 mg 1214 | 20 mg 1358 | 150 mg 711 | 2400 mg 207 | 1000 mg 766 |
| Autonomic Nervous System Disorders | ||||||
| Hypertension | 0.6 | 1.6 | 2.1 | 2.5 | 2.4 | 1.7 |
| Body as a Whole | ||||||
| Back pain | 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 |
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, angina pectoris, arrhythmia, cardiomyopathy, congestive heart failure, coronary artery disorder, heart murmur, hypotension
Central, peripheral nervous system: Cerebrovascular disorder, hypertonia, hypoesthesia, migraine, neuralgia, neuropathy, paresthesia, 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, pneumonia, pharyngitis, pleurisy, rhinitis
Skin and appendages: Acne, alopecia, dermatitis, dermatitis fungal, eczema, photosensitivity allergic reaction, pruritus, rash erythematous, 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, conjunctivitis, eye pain, keratitis, vision abnormal
White cell and RES disorders: Eosinophilia, leukopenia, leukocytosis, lymphadenopathy, lymphangitis, lymphopenia
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 encephalopathy, 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
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)
Gastrointestinal: Pancreatitis
Skin and appendages: Erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
OVERDOSAGE
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare.
Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Hemodialysis removed only about 2% of administered valdecoxib from the systemic circulation of 8 patients with end-stage renal disease and, based on its degree of plasma protein binding (>98%), dialysis is unlikely to be useful in overdose. Forced diuresis, alkalinization of urine, or hemoperfusion also may not be useful due to high protein binding.
DOSAGE AND ADMINISTRATION
Osteoarthritis and Adult Rheumatoid Arthritis
The recommended dose of BEXTRA Tablets for the relief of the signs and symptoms of arthritis is 10 mg once daily.
Primary Dysmenorrhea
The recommended dose of BEXTRA Tablets for treatment of primary dysmenorrhea is 20 mg twice daily, as needed.
HOW SUPPLIED
BEXTRA Tablets 10 mg are white, film-coated, and capsule-shaped, debossed "10" on one side with a four pointed star shape on the other, supplied as:
| NDC Number | Size |
|---|---|
| 0025-1975-31 | Bottle of 100 |
| 0025-1975-51 | Bottle of 500 |
| 0025-1975-34 | Carton of 100 unit dose |
BEXTRA Tablets 20 mg are white, film-coated, and capsule-shaped, debossed "20" on one side with a four pointed star shape on the other, supplied as:
| NDC Number | Size |
|---|---|
| 0025-1980-31 | Bottle of 100 |
| 0025-1980-51 | Bottle of 500 |
| 0025-1980-34 | Carton of 100 unit dose |
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [See USP Controlled Room Temperature].
Rx only
LAB-0266-7.0