|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====
====Precautions====
* Description
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.
<!--Adverse Reactions-->
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.
<!--Clinical Trials Experience-->
Hepatic Effects
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
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.
=====Body as a Whole=====
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.
=====Cardiovascular=====
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.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding.
=====Digestive=====
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=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 ≥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.
: [[File:Valdecoxib Adv eff.png|none|500px]]
=====Endocrine=====
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
|postmarketing=* 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)
|drugInteractions=* 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 vitro studies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 (IC50 = 6 µg/mL or 19 µM) and 2C9 (IC50 = 13 µg/mL or 41 µM), and a weak inhibitor of CYP 2D6 (IC50 = 31 µg/mL or 100 µM) and 3A4 (IC50 = 44 µg/mL or 141 µM).
=====Hematologic and Lymphatic=====
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 vitro aspirin-mediated inhibition of arachidonate- or collagen-stimulated platelet aggregation.
=====Metabolic and Nutritional=====
Methotrexate
Valdecoxib 10 mg BID did not show a significant effect on the plasma exposure or renal clearance of methotrexate.
ACE-inhibitors
=====Musculoskeletal=====
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.
=====Neurologic=====
Anticonvulsants (Phenytoin)
Steady state plasma exposure (AUC) of valdecoxib (40 mg BID for 12 days) was decreased by 27% when coadministered with multiple doses (300 mg QD for 12 days) of phenytoin (a CYP 3A4 inducer). Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin (a CYP 2C9 and CYP 2C19 substrate).
Drug interaction studies with other anticonvulsants have not been conducted. Routine monitoring should be performed when therapy with BEXTRA is either initiated or discontinued in patients on anticonvulsant therapy.
=====Respiratory=====
Dextromethorphan
Dextromethorphan is primarily metabolized by CYP 2D6 and to a lesser extent by 3A4. Coadministration with valdecoxib (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, valdecoxib is a weak inhibitor of 2D6. Even so, dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary.
Lithium
=====Skin and Hypersensitivy Reactions=====
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 (450 mg 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 coadministration 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.
=====Special Senses=====
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 fluconazole and 38% when coadministered with ketoconazole.
Glyburide
=====Urogenital=====
Glyburide is a CYP 2C9 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. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (5 mg QD) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (10 mg glyburide BID) resulted in 21% increase in glyburide AUC(0–12hr) and a 16% increase in glyburide Cmax leading to a 16%decrease in glucose AUC(0–24hr). Insulin parameters were not affected. Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg/dL, dose adjustment for glyburide (5 mg QD and 10 mg BID) with valdecoxib coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg valdecoxib (e.g., 40 mg BID) has not been studied.
Omeprazole
Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Valdecoxib steady state plasma concentrations (40 mg BID) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with valdecoxib increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib. However, because higher doses (up to 360 mg QD) of omeprazole are tolerated in Zollinger-Ellison (ZE) patients, no dose adjustment for omeprazole is recommended at current doses. Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied.
=====Miscellaneous=====
Oral Contraceptives
Valdecoxib (40 mg BID) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg combination, Ortho-Novum 1/35®). Coadministration of valdecoxib and Ortho-Novum 1/35® increased the exposure of norethindrone and ethinyl estradiol by 20% and 34%, respectively. Although there is little risk for loss of contraceptive efficacy, the clinical significance of these increased exposures in terms of safety is not known. These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib.
Diazepam
<!--Drug Interactions-->
Diazepam (Valium®) is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg BID) was increased by 28% following administration of valdecoxib (40 mg BID) for 12 days, while plasma exposure of valdecoxib (40 mg BID) was not substantially increased following administration of diazepam (10 mg BID) for 12 days. Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments, patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance. Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|FDAPregCat=C
|useInPregnancyFDA=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 20 mg 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 10 mg/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 ≥10 mg/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 ≥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.
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInLaborDelivery=* 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.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInNursing=* 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.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInPed=* Safety and effectiveness of BEXTRA in pediatric patients below the age of 18 years have not been evaluated.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGeri=* 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.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
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|administration=* Oral
|administration=* Oral
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
|monitoring=* If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable
* 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.
* Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding.
* Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration.
* Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium.
* Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
<!--Overdosage-->
|overdose====Acute Overdose===
|overdose=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.
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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.
<!--Pharmacology-->
<!--Drug box 2-->
|drugBox=<!--Mechanism of Action-->
|drugBox=<!--Mechanism of Action-->
|mechAction=*
|mechAction=*
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<!--Nonclinical Toxicology-->
<!--Nonclinical Toxicology-->
|nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
|nonClinToxic=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.
<!--Clinical Studies-->
<!--Clinical Studies-->
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|howSupplied=*
|howSupplied=*
|packLabel=<!--Patient Counseling Information-->
|packLabel=<!--Patient Counseling Information-->
|fdaPatientInfo=There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
|fdaPatientInfo=* 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.
<!--Precautions with Alcohol-->
In late pregnancy, BEXTRA should be avoided because it may cause premature closure of the ductus arteriosus.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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Black Box Warning
Serious Skin Reactions:
See full prescribing information for complete Boxed Warning.
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.
Overview
Valdecoxib is a Cyclooxygenase-2 Inhibitor that is FDA approved for the treatment of osteoarthritis, adult rheumatoid arthritis and primary dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
For relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.
For the treatment of primary dysmenorrhea
Dosage
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valdecoxib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Valdecoxib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Valdecoxib in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valdecoxib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Valdecoxib in pediatric patients.
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.
Warnings
Serious Skin Reactions:
See full prescribing information for complete Boxed Warning.
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.
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.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding.
Adverse Reactions
Clinical Trials Experience
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 ≥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.
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
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)
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 vitro studies indicate that valdecoxib is a moderate inhibitor of CYP 2C19 (IC50 = 6 µg/mL or 19 µM) and 2C9 (IC50 = 13 µg/mL or 41 µM), and a weak inhibitor of CYP 2D6 (IC50 = 31 µg/mL or 100 µM) and 3A4 (IC50 = 44 µg/mL or 141 µM).
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 vitro aspirin-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 (Phenytoin)
Steady state plasma exposure (AUC) of valdecoxib (40 mg BID for 12 days) was decreased by 27% when coadministered with multiple doses (300 mg QD for 12 days) of phenytoin (a CYP 3A4 inducer). Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration. Valdecoxib did not have a statistically significant effect on the pharmacokinetics of phenytoin (a CYP 2C9 and CYP 2C19 substrate).
Drug interaction studies with other anticonvulsants have not been conducted. 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 valdecoxib (40 mg BID for 7 days) resulted in a significant increase in dextromethorphan plasma levels suggesting that, at these doses, valdecoxib is a weak inhibitor of 2D6. Even so, dextromethorphan plasma concentrations in the presence of high doses of valdecoxib were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers suggesting that dose adjustment is not necessary.
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 (450 mg 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 coadministration 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 fluconazole and 38% when coadministered with ketoconazole.
Glyburide
Glyburide is a CYP 2C9 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. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (5 mg QD) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and insulin levels) of glyburide. Coadministration of valdecoxib (40 mg BID (day 1) and 40 mg QD (days 2–7)) with glyburide (10 mg glyburide BID) resulted in 21% increase in glyburide AUC(0–12hr) and a 16% increase in glyburide Cmax leading to a 16%decrease in glucose AUC(0–24hr). Insulin parameters were not affected. Because changes in glucose concentrations with valdecoxib coadministration were within the normal variability and individual glucose concentrations were above or near 70 mg/dL, dose adjustment for glyburide (5 mg QD and 10 mg BID) with valdecoxib coadministration (up to 40 mg QD) is not indicated. Coadministration of glyburide with doses higher than 40 mg valdecoxib (e.g., 40 mg BID) has not been studied.
Omeprazole
Omeprazole is a CYP 3A4 substrate and CYP 2C19 substrate and inhibitor. Valdecoxib steady state plasma concentrations (40 mg BID) were not affected significantly with multiple doses of omeprazole (40 mg QD). Coadministration with valdecoxib increased exposure of omeprazole (AUC) by 46%. Drugs whose absorption is sensitive to pH may be negatively impacted by concomitant administration of omeprazole and valdecoxib. However, because higher doses (up to 360 mg QD) of omeprazole are tolerated in Zollinger-Ellison (ZE) patients, no dose adjustment for omeprazole is recommended at current doses. Coadministration of valdecoxib with doses higher than 40 mg QD omeprazole has not been studied.
Oral Contraceptives
Valdecoxib (40 mg BID) did not induce the metabolism of the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg combination, Ortho-Novum 1/35®). Coadministration of valdecoxib and Ortho-Novum 1/35® increased the exposure of norethindrone and ethinyl estradiol by 20% and 34%, respectively. Although there is little risk for loss of contraceptive efficacy, the clinical significance of these increased exposures in terms of safety is not known. These increased exposures of norethindrone and ethinyl estradiol should be taken into consideration when selecting an oral contraceptive for women taking valdecoxib.
Diazepam
Diazepam (Valium®) is a CYP 3A4 and CYP 2C19 substrate. Plasma exposure of diazepam (10 mg BID) was increased by 28% following administration of valdecoxib (40 mg BID) for 12 days, while plasma exposure of valdecoxib (40 mg BID) was not substantially increased following administration of diazepam (10 mg BID) for 12 days. Although the magnitude of changes in diazepam plasma exposure when coadministered with valdecoxib were not sufficient to warrant dosage adjustments, patients may experience enhanced sedative side effects caused by increased exposure of diazepam under this circumstance. Patients should be cautioned against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.
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 20 mg 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 10 mg/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 ≥10 mg/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 ≥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.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valdecoxib in women who are pregnant.
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.
Geriatic 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.
Gender
There is no FDA guidance on the use of Valdecoxib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Valdecoxib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Valdecoxib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Valdecoxib in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valdecoxib in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Valdecoxib in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
If therapy with BEXTRA must be initiated, close monitoring of the patient's kidney function is advisable
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.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding.
Patients already stabilized on valdecoxib should be closely monitored for loss of symptom control with phenytoin coadministration.
Lithium serum concentrations should be monitored closely when initiating or changing therapy with BEXTRA in patients receiving lithium.
Anticoagulant therapy should be monitored, particularly during the first few weeks, after initiating therapy with BEXTRA in patients receiving warfarin or similar agents.
IV Compatibility
There is limited information regarding IV Compatibility of Valdecoxib in the drug label.
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.
Pharmacology
There is limited information regarding Valdecoxib Pharmacology in the drug label.
There is limited information regarding Pharmacodynamics of Valdecoxib in the drug label.
Pharmacokinetics
There is limited information regarding Pharmacokinetics of Valdecoxib in the drug label.
Nonclinical Toxicology
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.
Clinical Studies
There is limited information regarding Clinical Studies of Valdecoxib in the drug label.
How Supplied
Storage
There is limited information regarding Valdecoxib Storage in the drug label.
Images
Drug Images
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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.
Precautions with Alcohol
Alcohol-Valdecoxib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
