Valdecoxib

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Soluble in methanol and ethanol; freely soluble in organic solvents and alkaline (pH=12) aqueous solution

Relatively insoluble in water (10 ug/mL) at 25 °C and pH 7

>47.2 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Analgesic Agents; Anti-inflammatory Agents, Nonsteroidal

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Warning

H361 (97.4%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P260, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 39 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl valdecoxib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Repr. 2 (100%)

Repr. 2 (97.4%)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Valdecoxib produced significant decreases 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.

In clinical trials, concurrent use administration of valdecoxib 20 mg with multiple dose 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.

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.

Concurrent use /of angiotensin-converting enzyme (ACE) inhibitors/ with valdecoxib may decrease the antihypertensive effects of ACE inhibitors; also, risk of renal failure is increased in patients taking these medications.

For more Interactions (Complete) data for VALDECOXIB (14 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 190,000(SRC), determined from a structure estimation method(2), indicates that valdecoxib is expected to be immobile in soil(SRC). Volatilization of valdecoxib from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.2X10-11 atm-cu m/mole(SRC), determined using a fragment constant estimation method(3). Valdecoxib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-10 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 190,000(SRC), determined from a structure estimation method(2), indicates that valdecoxib is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.2X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 23(SRC), from an estimated log Kow of 2.67(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), valdecoxib, which has an estimated vapor pressure of 4.6X10-10 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase valdecoxib may be removed from the air by wet and dry deposition(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for valdecoxib can be estimated to be 190,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that valdecoxib is expected to be immobile in soil.

/SIGNS AND SYMPTOMS/ Symptoms of overdose may include lethargy, drowsiness, nausea, vomiting, and epigastric pain. These are usually reversible with supportive treatment. GI bleeding, hypertension, acute renal failure, respiratory depression, and coma may occur.Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

/SIGNS AND SYMPTOMS/ Serious, potentially life-threatening skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN), have been reported during postmarketing surveillance of valdecoxib. Fatalities due to Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported. While serious reactions may occur at any time during therapy with valdecoxib, the risk of such reactions appears to be highest within the first 2 weeks of therapy. While patients with a history of sulfonamide hypersensitivity may be at greater risk for skin reactions, patients without such a history also are at risk for serious skin reactions. These reactions are rare but have been reported at a greater frequency with valdecoxib than with other selective COX-2 inhibitors (e.g., celecoxib). Discontinue valdecoxib at the first appearance of a rash or any other manifestation of hypersensitivity.

/HUMAN EXPOSURE STUDIES/ Risk of potentially fatal GI ulceration, bleeding, and perforation. Most studies indicate less risk of GI ulceration than prototypical /SRP: NSAIDs/; however, the relative risk remains to be established. Use with caution in patients at risk for GI bleeding (e.g., history of GI bleeding or ulceration, treatment with oral corticosteroids or anticoagulants, longer duration of /SRP: NSAID/ therapy, geriatric patients, debilitation, smokers, or alcohol dependence). Consider alternative therapy in those at high risk for GI bleeding. ...

/HUMAN EXPOSURE STUDIES/ Severe (rarely fatal) anaphylactoid reactions have occurred in patients receiving /SRP: NSAIDs/, and anaphylactoid reactions (e.g., anaphylaxis, angioedema) have been reported during postmarketing surveillance of valdecoxib. Such reactions occurred in patients with or without a history of allergic-type reactions to sulfonamides. ...Cross-sensitivity between aspirin and other /SRP: NSAIDs/ may occur. Do not use in patients with bronchospastic aspirin sensitivity. Avoid use in patients with aspirin triad. Caution in patients with preexisting asthma, as bronchospasms may occur.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Valdecoxib

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 23 was calculated for valdecoxib(SRC), using an estimated log Kow of 2.67(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low.

The Henry's Law constant for valdecoxib is estimated as 2.2X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that valdecoxib is expected to be essentially nonvolatile from water surfaces(2). Valdecoxib's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Valdecoxib is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-10 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ 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 or in mice given oral doses up to 25 mg/kg/day for males and 50 mg/kg/day for females for two years.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Valdecoxib did not impair male rat fertility at oral doses up to 9.0 mg/kg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In female rats, a decrease in ovulation with increased pre- and post-implantation loss resulted in decreased live embryos/fetuses at doses > or = 2 mg/kg/day. The effects on female fertility were reversible. This effects is expected with inhibition of prostaglandin synthesis and is not the result of irreversible alteration of female reproductive function.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The incidence of fetuses with skeletal anomalies such as semi-bipartite thoracic vertebra centra and fused sternebrae was slightly higher in rabbits at the oral dose of 40 mg/kg/day throughout organogenesis. Valdecoxib was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day.

/GENOTOXICITY/ In animal studies valdecoxib was not mutagenic in the Ames test or a mutation assay in Chinese hamster ovary (CHO) cells. No clastogenic effect was observed in the chromosome aberration assay in CHO cells or in in vivo micronucleus test in rat bone marrow.

Occupational exposure to valdecoxib may occur through inhalation and dermal contact with this compound at workplaces where valdecoxib is produced or used. The general population is exposed via ingestion of valdecoxib by its use as a drug. (SRC)

Valdecoxib's production and use as an anti-inflammatory may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.6X10-10 mm Hg at 25 °C indicates valdecoxib will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase valdecoxib will be removed from the atmosphere by wet and dry deposition. If released to soil, valdecoxib is expected to have no mobility based upon an estimated Koc of 190,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.2X10-11 atm-cu m/mole. Valdecoxib is not expected to volatilize from dry soil surfaces based upon its vapor pressure. If released into water, valdecoxib is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 23 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to valdecoxib may occur through inhalation and dermal contact with this compound at workplaces where valdecoxib is produced or used. The general population is exposed via ingestion of valdecoxib by its use as a drug. (SRC)

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl valdecoxib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

M - Musculo-skeletal system

QM - Musculo-skeletal system

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism.

Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit platelet aggregation.

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) with antiinflammatory, analgesic, and antipyretic therapeutic effects. 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. However, unlike most NSAIDs, valdecoxib does not inhibit cyclooxygenase-1 (COX-1) isoenzyme in humans at therapeutic concentrations.

8-11 hours

Elimination: 8 to 11 hours. Terminal: 8.11 hours.

Hepatic (involves CYP3A4 and 2C9)

One active metabolite of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent also undergoes extensive metabolism and constitutes <2% of the valdecoxib dose excreted in the urine and feces. Due to the low concentration in the systemic circulation, it is not likely to contribute significantly to the efficacy profile of valdecoxib.

In humans, valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and 2C9) and non-P450 dependent pathways (i.e., glucuronidation).

Valdecoxib has known human metabolites that include 4-[3-(3-hydroxyphenyl)-5-methyl-1,2-oxazol-4-yl]benzene-1-sulfonamide and 4-[5-(hydroxymethyl)-3-phenyl-1,2-oxazol-4-yl]benzene-1-sulfonamide.

Oral bioavailability is 83%.

Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide.

86 L

oral cl=6 L/h

At recommended doses, the mean oral bioavailability is 83%. The peak plasma concentration and area under the plasma concentration-time curve are roughly proportional across the clinical dose range. 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.

Time to peak concentration: Approximately 3 hours. Note: Time to peak concentration was delayed by 1 to 2 hours when administered with a high fat meal.

Medication

Use (kg) in USA (2002): 1990

Information available in 2005 indicated that Valdecoxib was used in the manufacture of pharmaceutical preparations in the following countries: Austria, Belgium, Chile, Colombia, Germany, India, Singapore, Switzerland, United Kingdom, United States (1,2)