Professional Information
Valdecoxib (Systemic)
VA CLASSIFICATION
Primary: MS102
Commonly used brand name(s): Bextra.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antirheumatic (nonsteroidal anti-inflammatory)—
Antidysmenorrheal—
Indications
Accepted
Rheumatoid arthritis, adult (treatment); or
Osteoarthritis (treatment)—Valdecoxib is indicated for the relief of the signs and symptoms of osteoarthritis and adult rheumatoid arthritis.{01}
Dysmenorrhea, primary (treatment)—Valdecoxib is indicated for treatment {02} of primary dysmenorrhea {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
314.36 {01}
Solubility
Relatively insoluble in water; soluble in methanol and ethanol; freely soluble in organic solvents and alkaline aqueous solutions {01}.
Mechanism of action/Effect:
Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic therapeutic effects {01}. It has been proposed that valdecoxib inhibits the activity of the enzyme cyclooxygenase-2 (COX-2), resulting in a decreased formation of precursors of prostaglandins {01}. However, unlike most NSAIDs, valdecoxib does not inhibit cyclooxygenase-1 (COX-1) isoenzyme in humans at therapeutic concentrations {01}.
Other actions/effects:
Valdecoxib has anti-inflammatory and antipyretic actions that, together with its analgesic effects, may diminish the utility of these diagnostic signs in detecting complications presumed noninfectious, painful conditions {02}.
Absorption:
At recommended doses, the mean oral bioavailability is 83% {01}. The peak plasma concentration and area under the plasma concentration–time curve are roughly proportional across the clinical dose range {01}. Valdecoxib may be coadministered with meals. Peak plasma concentrations and extent of absorption were not affected after valdecoxib was taken with a high fat meal. {01}.
Distribution:
At steady state, the apparent volume of distribution is about 86 L {01}.
Protein binding:
Very high (98%)
{01}
.
Biotransformation:
Hepatic via cytochrome P450 (isoenzymes 2C9 and 3A4) and non-P450 dependent pathways (glucuronidation) to one active metabolite, which does not likely contribute to the clinical efficacy due lower potency as a COX-2 inhibitor compared to parent product and low concentrations in the systemic circulation.{01}.
Half-life:
Elimination— 8 to 11 hours {02}
Terminal— 8.11 hours {01}.
Time to peak concentration:
Approximately 3 hours {01}.
Note: Time to peak plasma concentration was delayed by 1 to 2 hours when administered with a high fat meal.{01}
Peak serum concentration:
At steady state after 10 mg once daily for 14 days—161 nanograms per mL {01}.
Elimination:
Approximately 70% of a valdecoxib dose is eliminated in the urine as metabolites. Approximately 5% is excreted in the feces and urine unchanged {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Valdecoxib may cause bronchoconstriction or anaphylaxis in aspirin-sensitive asthmatics, especially those with the "aspirin triad" symptomatology of rhinitis with or without nasal polyps, asthma, and have experienced severe bronchospasm after taking aspirin or other nonsteroidal anti-inflammatory {01}. Patients sensitive to other nonsteroidal anti-inflammatory drugs or aspirin may be sensitive valdecoxib also {01}.
Carcinogenicity
In a 2-year carcinogenicity study in male and female rats given oral doses of valdecoxib of up to 7.5 mg per kg of body weight (mg/kg) and 1.5 mg/kg, respectively (approximately two to six times the human exposure based on the area under the plasma concentration–time curve [AUC] at 20 mg daily), no carcinogenic effects were observed {01}. In a 2-year carcinogenicity study in male and female mice receiving oral doses of valdecoxib of up to 25 mg/kg and 50 mg/kg, respectively (approximately 0.6 to 2.4 times the human exposure based on the AUC at 20 mg daily), no carcinogenic effects were observed.{01}
Mutagenicity
In animal studies valdecoxib was not mutagenic in the Ames test or a mutation assay in Chinese hamster ovary (CHO) cells{01}. No clastogenic effect was observed in the chromosome aberration assay in CHO cells or in in vivo micronucleus test in rat bone marrow.{01}
Pregnancy/Reproduction
Fertility—
In studies done on female rats, there was a decrease in ovulation with increased pre- and post-implantation loss resulting in decreased live embryos/fetuses at doses greater than or equal to 2 mg/kg per day (approximately 2-fold the human exposure at 20 mg daily based on AUC). The effects on female rat fertility were reversible. In male rats receiving oral doses up to 9 mg/kg (approximately 3-fold to 6-fold the human exposure at 20 mg daily based on AUC), no evidence of fertility impairment was observed{01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done.{01} Valdecoxib may cause premature closure of the ductus arteriosus.{01} Therefore, use of valdecoxib is not recommended during the third trimester of pregnancy.{01}
Valdecoxib crosses the placenta in rats and rabbits. No teratogenic effects were observed in rats receiving oral doses of valdecoxib at 10 mg/kg per day (approximately 19-fold the human exposure at 20 mg daily based on AUC).{01} In rabbits receiving 40 mg/kg per day (approximately 72-fold the human exposure at 20 mg daily based on AUC), a slight increase in the incidence of vertebral malformations was observed.{01} Studies in rats and rabbits receiving oral doses of valdecoxib of greater than 10 mg/kg per day and 40 mg/kg per day, respectively, reported increased preimplantation and postimplantation losses and reduced embryo and fetal survival.{01} These changes were expected with inhibition of prostaglandin synthesis.{01} However, these changes are not the result of permanent alteration in female reproductive function.{01}
FDA Pregnancy Category C{01}.
Labor and delivery—
The effect of valdecoxib on labor and delivery in pregnant women is unknown {01}.
No evidence of delayed labor or parturition was found in rats receiving oral doses of valdecoxib of up to 10 mg/kg (approximately 19–fold the human exposure based on AUC at 20 mg per day) {01}.
Breast-feeding
It is not known whether valdecoxib is distributed into human breast milk.{01} Valdecoxib and its active metabolite are distributed into the milk of lactating rats.{01}
Pediatrics
Appropriate studies on the relationship of age to the effects of valdecoxib have not been performed in the pediatric population.{01} Safety and efficacy in children younger than 18 years of age have not been established.{01}
Geriatrics
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the use of valdecoxib in geriatric patients.{01} No dose adjustment is needed based on age.{01}
Pharmacogenetics
Pharmacokinetic differences due to race and gender have not been identified in clinical and pharmacokinetic studies conducted to date.{01}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Angiotensin-converting enzyme (ACE) inhibitors (concurrent use with valdecoxib may decrease the antihypertensive effects of ACE inhibitors; also, risk of renal failure is increased in patients taking these medications {01})
Anticoagulants, coumarin- or indanedione-derivative (single and multiple dose crossover studies of valdecoxib 40 mg twice daily for seven days with warfarin 1 to 8 mg daily were associated with significant increases in plasma exposures of warfarin and an increase in prothrombin time (measured as INR); while mean INR values were only slightly increased, the day-to-day variability in individual INR values increased; monitoring of INR is recommended for the first few weeks after valdecoxib is initiated or the dose is changed {01})
» Aspirin (concurrent use with valdecoxib may increase the risk for gastrointestinal [GI] ulcerations or GI complications {01})
Dextromethorphan (concurrent administration with valdecoxib 40 mg twice daily for 7 days resulted in a significant increase in dextromethorphan plasma levels, suggesting that, at these doses, valdecoxib is a weak inhibitor of P450 2D6.)
Diuretics, thiazide or
Furosemide (nonsteroidal anti-inflammatory drugs may decrease the natriuretic effects of diuretics, possibly by inhibiting renal prostaglandin synthesis; also, risk of renal failure is increased in patients taking these medications {01})
» Fluconazole or
» Ketoconazole (in clinical trials, concurrent administration of valdecoxib 20 mg with multiple doses of ketoconazole and fluconazole produced increased plasma exposure of valdecoxib by 62% when coadministered with fluconazole and 38% when coadministered with ketoconazole. the increase in plasma concentration of valdecoxib was due to the inhibition of valdecoxib metabolism via P450 2C9 and 3A4 by fluconazole and ketoconazole. {01})
» Lithium (Valdecoxib produced significant decreased in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone; therefore, monitoring of lithium concentrations for signs of lithium toxicity is recommended during concurrent use; however, lithium has no effect on valdecoxib pharmacokinetics {01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Alanine aminotransferase (ALT [SGPT]), serum and
Aspartate aminotransferase (AST [SGOT]), serum (serum values may be increased; liver function test abnormalities may return to normal despite continued use; however, if significant abnormalities occur, clinical signs and symptoms consistent with liver disease develop, or systemic manifestations such as eosinophilia or rash occur, use of valdecoxib should be discontinued {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problems exist:
» Allergic reaction, severe, such as anaphylaxis, induced by aspirin or other NSAIDS, history of
» Asthma with rhinitis (with or without nasal polyps) or severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs {02} (aspirin triad), (high risk of severe allergic reaction{01})
Risk-benefit should be considered when the following medical problems exist
Anemia (may be exacerbated {01})
Asthma, pre-existing ( caution is recommended when using in patients with aspirin— sensitive asthma since cross reactivity between aspirin and other NSAIDS has been reported in aspirin-sensitive patients {01})
Alcoholism, active or
» Gastrointestinal bleeding, active or pre-existing or
» Peptic ulcer disease, active or pre-existing or
Poor general health or
Tobacco use (Other co-morbid conditions that may increase the risk of GI bleeding. Valdecoxib should be used with extreme caution in patients with peptic ulcer disease or gastrointestinal bleeding; dosage adjustment is recommended to minimize potential risk of gastrointestinal bleeding. {01})
Compromised cardiac heart function or
» Congestive heart disease or
Edema, pre-existing or
Hypertension (Conditions predisposing to and/or exacerbated by fluid retention, valdecoxib may cause additive fluid retention or edema; also, risk of renal failure is increased in patients with congestive heart disease; valdecoxib should be initiated at the lowest dose in these patients{01})
Dehydrated patients (Caution should be used when initiating treatment with valdecoxib in patients with considerable dehydration. It is recommended to rehydrate patients first.{01})
» Hepatic function impairment (hepatotoxicity, as indicated by significant abnormalities in liver function tests, may be more likely to occur in patients with pre-existing hepatic function impairment; careful monitoring is recommended {01})
(risk of renal failure is increased in these patients; careful monitoring is recommended)
(studies have shown increased area under the plasma concentration–time curve in patients with moderate hepatic impairment [130%]; therefore, dosage adjustment and careful monitoring are recommended in patients with moderate hepatic impairment; however, use in patients with severe hepatic impairment is not recommended {01})
» Renal function impairment, advanced (long-term studies in patients with severe renal disease have not been done; use of valdecoxib is not recommended in these patients; however, if valdecoxib is used in patients with severe renal impairment, close monitoring is recommended {01})
» Sensitivity to valdecoxib{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase ALT [SGPT], serum and
Aspartate aminotransferase AST [SGOT], serum (careful monitoring is recommended in patients with signs and symptoms of hepatic function impairment; if elevations persist, discontinuation of therapy may be necessary {01})
Hematocrit or
Hemoglobin (monitoring is recommended in patients who have developed signs and symptoms of anemia or blood loss during prolonged therapy with valdecoxib {01})
Note: Physicians should monitor patients for signs and symptoms of gastrointestinal bleeding.{01}
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent or rare
Anemia (pale skin; troubled breathing with exertion; unusual bleeding or bruising; unusual tiredness or weakness)
edema, peripheral (bloating or swelling of face, arms, hands, lower legs; rapid weight gain; tingling of the hands or feet)
gastrointestinal ulceration or bleeding ( bloody, black, or sticky stools; severe stomach pain; vomiting of blood or material that looks like coffee grounds)
hepatic reactions (flu-like symptoms; nausea; unusual tiredness; yellow skin or eyes)—jaundice, fatal fulminant hepatitis, liver necrosis and hepatic failure
hypertension ( blurred vision; dizziness,; nervousness ; pounding in the ears)
influenza-like symptoms (chills; fever; muscle aches and pains)
renal toxicity (blood in urine; decreased or painful urination; swelling of feet or lower legs)
{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Abdominal pain (stomach pain)
diarrhea
dyspepsia (acid or sour stomach; belching ; indigestion; heartburn)
headache
nausea
{01}
Upper respiratory tract infection{01} (ear congestion ; cough; fever; sore throat)
Incidence less frequent
Abdominal fullness
back pain
dizziness
flatulence (bloating in the abdomen; excess gas)
injury, accidental
myalgia (muscle pain)
rash
sinusitis ( stuffy or runny nose; headache)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute renal failure (shortness of breath, troubled breathing, tightness in chest and/or wheezing; sudden decrease in amount of urine; swelling of face, fingers, and/or lower legs; continuing thirst; unusual tiredness or weakness; weight gain)
drowsiness
epigastric pain (stomach pain), gastrointestinal bleeding (bloody or black, tarry stools; vomiting of blood or material that looks like coffee grounds)
hypertension (dizziness; headache, severe or continuing)
lethargy ( unusual feeling or tiredness or weakness)
nausea and/or vomiting
respiratory depression (difficulty breathing)
Treatment of overdose
There is no specific antidote.{01}
Hemodialysis is not effective for valdecoxib. Forced diuresis, alkalinization of urine or hemoperfusion also may not be useful due to high protein binding{01}.
Supportive care—Monitoring and supporting vital functions. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {01}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Valdecoxib (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to valdecoxib
Allergies to aspirin or any other nonsteroidal anti-inflammatory drugs (NSAIDs)
Pregnancy—Use of valdecoxib during late pregnancy is not recommended because it may cause premature closure of the ductus arteriosus
Other medications, especially aspirin, fluconazole, ketoconazole or lithium.
Other medical problems, especially allergic reaction induced by aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), asthma (aspirin triad: aspirin-induced bronchospasm or rhinitis with or without polyps in asthmatics), gastrointestinal bleeding (active or prior history of), peptic ulcer disease active or prior history of, congestive heart disease, hepatic function impairment, or renal function impairment (advanced).
Proper use of this medication
» Not taking more medication than prescribed
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses
Proper storage
Precautions while using this medication
Regular visits to physician during prolonged therapy
» Possibility that use of alcohol may increase the risk of ulceration
» Importance of reporting symptoms of edema, gastrointestinal bleeding or ulceration, unusual weight gain, or skin rash to physician immediately
» Possibility that liver dysfunction may be exacerbated
» Possibility of anaphylaxis
Side/adverse effects
Signs of potential side effects, especially anemia, peripheral edema, gastrointestinal ulceration or bleeding, hepatic reactions (jaundice, fatal fulminant hepatitis, liver necrosis and hepatic failure), hypertension, influenza-like symptoms, or renal toxicity.
General Dosing Information
Valdecoxib should not be substituted for corticosteroid treatment or treatment of corticosteroid insufficiency.{01}
Valdecoxib should not be substituted for aspirin for cardiovascular prophylaxis due to a lack of anti-platelet effect of valdecoxib.{01}
Antacids did not interfere with the rate or extent of valdecoxib absorption.{01}
Diet/Nutrition
Valdecoxib may be taken with or without food {01}.
Oral Dosage Forms
VALDECOXIB TABLETS
Usual Adult Dose
Dysmenorrhea, primary
Oral, 20 mg twice daily as needed. {01}
Arthritis, rheumatoid adult
Oral, 10 mg once daily {01}.
Osteoarthritis
Oral, 10 mg once daily {01}.
Usual Pediatric Dose
Safety and efficacy have not been established. {01}
Usual Geriatric Dose
See Usual adult dose.
Strength(s) usually available
U.S.—
10 mg (Rx) [Bextra{01} ( croscarmellose sodium) (hydroxypropyl methylcellulose ) (lactose monohydrate) ( magnesium stearate) (microcrystalline cellulose ) (polyethylene glycol) ( polysorbate 80) (pregelatinized starch) (titanium dioxide)]
20 mg (Rx) [Bextra{01} ( croscarmellose sodium) (hydroxypropyl cellulose ) (lactose monohydrate) ( magnesium stearate) (microcrystalline cellulose ) (polyethylene glycol) ( polysorbate 80) (pregelatinized starch) (titanium dioxide)]
Packaging and storage:
Store between 25 °C (77 °F). Excursions permitted to 15–30°C (59–86°F){01}
Developed: 12/17/2001
Revised: 01/30/2002
References
- Product Information: Bextra™, valdecoxib. Pharmacia Corporation, Chicago, IL, (PI developed 11/2001) reviewed 11/2001.
- Manufacturer comment, 1/02
- Expert committee comment, 1/02
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