Side Effects of Bextra (valdecoxib)

Bextra (valdecoxib tablets) is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve the signs and symptoms of osteoarthritis and adult rheumatoid arthritis and to treat painful menstrual cramps (primary dysmenorrhea).  The brand name Bextra has been discontinued.

Common side effects of Bextra include

• headache,
• abdominal pain,
• indigestion/heartburn,
• upper respiratory tract infection,
• nausea,
• diarrhea,
• gas (flatulence),
• flu-like symptoms,
• dizziness,
• abdominal fullness, and
• sinus infection. 

Serious side effects of Bextra include

• serious gastrointestinal toxicity such as bleeding, ulceration and perforation of the stomach, small intestine or large intestine;
• serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis; and
• hypersensitivity reactions (anaphylactic reactions and angioedema) 

Drug interactions of Bextra include aspirin, which when taken with Bextra can increase the risk of gastrointestinal ulceration and complications.

Bextra may diminish the antihypertensive effect of ACE-inhibitors.

Bextra can reduce the diuretic effect of furosemide and thiazides.

Anticonvulsants may reduce the effectiveness of Bextra.

Bextra may increase levels of lithium and warfarin in the body.

Ketoconazole and fluconazole can increase concentrations of Bextra in the blood and increase risk of side effects.

Bextra when combined with oral contraceptives may increase concentrations of the contraceptives and the safety is not known.

Diazepam’s sedative side effects are increased when taken with Bextra.

There are no studies of Bextra in pregnant women. In late pregnancy, Bextra should be avoided because it may cause premature closure of the ductus arteriosus. Bextra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unknown if Bextra 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 breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother and the importance of nursing to the infant.

WARNING

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.

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).

Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction.

Patients should be informed of the warning signs and symptoms of hepatotoxicity such as

• 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.

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.

Table 4 Adverse Events with Incidence ≥2.0% in Valdecoxib Treatment Groups : Controlled Arthritis Trials of Three Months or Longer

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

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 ACEinhibitors.

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.