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Valdecoxib
Valdecoxib
Valdecoxib
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Valdecoxib
Clinical data
Trade namesBextra
Pregnancy
category
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability83%
Protein binding98%
MetabolismHepatic (CYP3A4 and 2C9 involved)
Elimination half-life8 to 11 hours
ExcretionRenal
Identifiers
  • 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.229.918 Edit this at Wikidata
Chemical and physical data
FormulaC16H14N2O3S
Molar mass314.36 g·mol−1
3D model (JSmol)
  • O=S(=O)(N)c3ccc(c2c(onc2c1ccccc1)C)cc3
  • InChI=1S/C16H14N2O3S/c1-11-15(12-7-9-14(10-8-12)22(17,19)20)16(18-21-11)13-5-3-2-4-6-13/h2-10H,1H3,(H2,17,19,20) checkY
  • Key:LNPDTQAFDNKSHK-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. It is a selective cyclooxygenase-2 inhibitor. It was patented in 1995.[2]

Valdecoxib was manufactured and marketed under the brand name Bextra by G. D. Searle & Company as an anti-inflammatory arthritis drug.[3] It was approved by the United States Food and Drug Administration (FDA) on November 20, 2001, to treat arthritis and menstrual cramps,[4][5] and was available by prescription in tablet form until 2005 when the FDA requested that Pfizer (Searle's parent company) withdraw Bextra from the American market.[6] The FDA cited "potential increased risk for serious cardiovascular (CV) adverse events," an "increased risk of serious skin reactions" and the "fact that Bextra has not been shown to offer any unique advantages over the other available NSAIDs."[6]

In 2009, Bextra was at the center of the "largest health-care fraud settlement and the largest criminal fine of any kind ever."[4][7] Pfizer paid a $2.3 billion civil and criminal fine. Pharmacia & Upjohn, a Pfizer subsidiary, violated the United States Food, Drug and Cosmetic Act for misbranding Bextra "with the intent to defraud or mislead."[3]

A water-soluble and injectable prodrug of valdecoxib, parecoxib, is marketed in the European Union under the tradename Dynastat.

Uses until 2005

[edit]

In the United States, the FDA approved valdecoxib for the treatment of osteoarthritis, adult rheumatoid arthritis, and primary dysmenorrhea.[8]

Valdecoxib was also used off-label for controlling acute pain and various types of surgical pain.[8]

Side effects and withdrawal from market

[edit]

On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA, citing an increased risk of heart attack and stroke and also the risk of a serious, sometimes fatal, skin reaction. This was a result of recent attention to prescription NSAIDs, such as Merck's Vioxx. Other reported side effects were angina and Stevens–Johnson syndrome.

Pfizer first acknowledged cardiovascular risks associated with Bextra in October 2004. The American Heart Association soon after was presented with a report indicating patients using Bextra while recovering from heart surgery were 2.19 times more likely to suffer a stroke or heart attack than those taking placebos.

In a large study published in The Journal of the American Medical Association in 2006, valdecoxib appeared less adverse for renal (kidney) disease and heart arrhythmia compared to Vioxx, but elevated renal risks were slightly suggested.[9]

2009 settlement for off-label uses promotions

[edit]

On September 2, 2009, the United States Department of Justice fined Pfizer $2.3 billion after one of its subsidiaries, Pharmacia & Upjohn Company, pleaded guilty to marketing four drugs, including Bextra, "with the intent to defraud or mislead."[10] Pharmacia & Upjohn admitted to criminal conduct in the promotion of Bextra, and agreed to pay the largest criminal fine ever imposed in the United States for any matter, $1.195 billion.[11] A former Pfizer district sales manager was indicted and sentenced to home confinement for destroying documents regarding the illegal promotion of Bextra.[12][13] In addition, a regional manager pleaded guilty to distribution of a misbranded product, and was fined $75,000 and 24 months on probation.[14]

The remaining $1 billion of the fine were paid to resolve allegations under the civil False Claims Act case and is the largest civil fraud settlement against a pharmaceutical company. Six whistleblowers were awarded more than $102 million for their role in the investigation.[15] Former Pfizer sales representative John Kopchinski acted as a qui tam relator and filed a complaint in 2004 outlining the illegal conduct in the marketing of Bextra.[16] Kopchinski was awarded $51.5 million for his role in the case because the improper marketing of Bextra was the largest piece of the settlement at $1.8 billion.[17]

Analytical methods

[edit]

Several HPLC-UV methods[18] have been reported for valdecoxib estimation in biological samples like human urine.[19][20] Valdecoxib has analytical methods for bioequivalence studies,[21][22] metabolite determination,[23][24][19] estimation of formulation,[25] and an HPTLC method for simultaneous estimation in tablet dosage form.[26]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Valdecoxib

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from Grokipedia
Valdecoxib is a potent, orally administered selective inhibitor of the enzyme (COX-2), functioning as a (NSAID) by blocking the conversion of to prostaglandins responsible for and , while sparing COX-1 to reduce gastrointestinal risks associated with traditional NSAIDs. Developed by G.D. Searle & Co. (later acquired by ) and marketed under the brand name Bextra, it was approved by the U.S. on November 16, 2001, for relieving signs and symptoms of and adult , as well as managing acute and primary . Despite initial promise as a safer alternative to nonselective NSAIDs due to lower rates of upper gastrointestinal ulcers, , and in clinical trials, valdecoxib's market trajectory was abruptly halted when voluntarily withdrew it worldwide on April 7, 2005, at the FDA's request. The withdrawal stemmed from post-marketing data revealing an elevated risk of serious cardiovascular thrombotic events, including and , comparable to that observed with (Vioxx), alongside reports of severe and potentially life-threatening skin reactions such as Stevens-Johnson syndrome and . These risks, which outweighed any demonstrated advantages over other NSAIDs in efficacy or overall safety, underscored broader concerns about COX-2 inhibitors' prothrombotic potential linked to imbalanced inhibition of vascular versus .

Pharmacology

Mechanism of Action

Valdecoxib selectively inhibits the (COX-2) isoform of the enzyme family, which catalyzes the conversion of to prostaglandin H2 (PGH2), a key precursor for prostanoids mediating , , and fever. By blocking this pathway, valdecoxib reduces the synthesis of downstream prostaglandins such as PGE2, thereby exerting , , and effects with minimal interference in COX-1-mediated processes like gastric mucosal protection and platelet aggregation. This selectivity arises from valdecoxib's noncovalent binding to the COX-2 active site, forming a stable enzyme-inhibitor complex facilitated by the larger hydrophobic pocket in COX-2 compared to COX-1, which accommodates the drug's isoxazole and sulfonamide moieties. In vitro assays demonstrate potent COX-2 inhibition with an IC50 of 0.005 μM for recombinant human COX-2, outperforming comparators like celecoxib (IC50 0.05 μM) and rofecoxib (IC50 0.5 μM). The COX-1/COX-2 IC50 selectivity ratio exceeds 60, indicating substantially greater affinity for COX-2 and reduced gastrointestinal toxicity relative to non-selective NSAIDs. Whole blood assays confirm this profile, with monocyte COX-2 inhibition occurring at concentrations far below those affecting platelet COX-1.

Pharmacokinetics and Metabolism

Valdecoxib exhibits rapid oral absorption, with peak plasma concentrations (Cmax) attained approximately 3 hours after dosing in healthy adults. Its absolute is 83%, indicating minimal first-pass . The demonstrate dose proportionality for area under the curve (AUC) and Cmax following single doses up to 400 mg, though multiple dosing above 10 mg twice daily results in greater-than-proportional increases in AUC. Steady-state concentrations are achieved by day 4 of repeated dosing. Food intake delays time to Cmax (Tmax) by 1-2 hours without altering overall exposure (AUC or Cmax), and antacids exert no clinically significant effect. The apparent at (Vss/F) is approximately 86 L, consistent with distribution into tissues beyond the vascular compartment. Valdecoxib is highly bound to plasma proteins (>98%) across a concentration range of 21-2384 ng/mL, with a blood-to-plasma concentration ratio of about 2.5:1 that remains stable over time. Metabolism occurs extensively in the liver, primarily through isoenzymes and , accounting for the majority of , with contributing an additional ~20% via non-P450 pathways. At least nine phase I metabolites have been identified in humans, including one pharmacologically that reaches concentrations ~10% of parent drug levels but exhibits lower potency as a COX-2 inhibitor. Elimination is predominantly renal, with less than 5% of the dose recovered unchanged in urine or feces; approximately 70% appears in urine as metabolites, and ~20% as the valdecoxib N-glucuronide conjugate. The apparent oral clearance (CL/F) is ~6 L/hr, and the mean terminal elimination half-life ranges from 8 to 11 hours, prolonging slightly with advanced age. In special populations, exposure (AUC) increases ~30% in elderly subjects (>65 years) and 130% in those with moderate hepatic impairment (Child-Pugh B), while renal impairment does not substantially alter clearance. No pharmacokinetic differences by race have been noted.

Clinical Uses and Efficacy

Approved Indications

Valdecoxib, marketed as Bextra, received FDA approval on November 16, 2001, for the relief of the of in adults, typically administered at 10 mg once daily. This indication was supported by five double-blind, randomized, controlled trials evaluating its efficacy in managing of the or , demonstrating reductions in and improved joint function comparable to other nonsteroidal anti-inflammatory drugs. The drug was also approved for the relief of signs and symptoms of adult , with a recommended dose of 10 mg once daily, or 20 mg for patients requiring additional effects. Clinical trials confirmed its ability to alleviate , , and in patients, positioning it as an alternative to traditional NSAIDs for those at risk of gastrointestinal complications. Additionally, valdecoxib was indicated for the treatment of primary , with dosing of 20 mg twice daily as needed, starting with the onset of symptoms. data from controlled studies showed it provided significant relief within one hour, with effects lasting up to 24 hours, outperforming in reducing menstrual cramping and associated discomfort. These approvals reflected its selective COX-2 inhibition profile, aimed at minimizing gastrointestinal side effects while targeting inflammatory pathways.

Comparative Efficacy Against Traditional NSAIDs

In randomized controlled trials for (RA), valdecoxib at doses of 20 mg or 40 mg once daily demonstrated efficacy comparable to 75 mg sustained-release twice daily, with no significant differences in American College of Rheumatology (ACR) response rates, pain scores, or functional improvements over 12 weeks. Similarly, valdecoxib 20 mg once daily showed equivalent improvements in ACR20 responder indices and tender/swollen joint counts relative to naproxen 500 mg twice daily in patients with active RA over 12 weeks. For (OA), valdecoxib 10 mg or 20 mg once daily provided pain relief and functional benefits equivalent to naproxen 500 mg twice daily, as measured by Western Ontario and McMaster Universities Index (WOMAC) scores and patient global assessments in 12-week trials. FDA-submitted confirmed valdecoxib's noninferiority to ibuprofen 800 mg three times daily and 75 mg twice daily in reducing OA pain and improving mobility. A of randomized controlled trials across OA and RA indicated that valdecoxib 10 mg and 20 mg daily doses were superior to but matched the efficacy of maximum recommended doses of nonselective NSAIDs like , ibuprofen, and naproxen, without evidence of superior or effects. These findings align with broader COX-2 inhibitor profiles, where selectivity does not confer greater potency over traditional NSAIDs in symptom control.

Safety and Risk Profile

Gastrointestinal Benefits

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, exhibited gastrointestinal (GI) benefits primarily through reduced inhibition of COX-1, the isoform responsible for protecting gastric mucosa via prostaglandin synthesis. Clinical trials demonstrated lower rates of upper GI adverse events, including dyspepsia, abdominal pain, and ulcers, compared to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). In a randomized controlled trial involving patients with osteoarthritis of the knee, valdecoxib at 10 mg or 20 mg once daily produced significantly fewer GI-related adverse events than diclofenac 75 mg twice daily, with the 20 mg dose showing improved tolerability (P = 0.035). Endoscopic studies further quantified these advantages. In healthy elderly volunteers receiving supratherapeutic doses (up to 40 mg daily for 7 days), valdecoxib was associated with gastroduodenal rates similar to (4%) and significantly lower than naproxen 500 mg twice daily (28%; P < 0.001). This reflects a class effect of COX-2 inhibitors, where valdecoxib reduced the incidence of endoscopic ulcers by sparing protective mucosal prostaglandins. Large-scale outcomes data aligned with these findings, showing COX-2 selective agents like valdecoxib conferred substantial risk reductions—approximately 50% to 60% fewer clinical upper events (e.g., ulcers, perforations, obstructions, or ) relative to nonselective NSAIDs in comparable populations. Single daily doses of valdecoxib 10 mg or 20 mg also demonstrated improved upper safety in broader contexts, with fewer discontinuations due to intolerance. These benefits were particularly relevant for patients with or at elevated risk, though co-administration with inhibitors or low-dose aspirin could modulate absolute risk reductions.

Cardiovascular Risks

Valdecoxib, a selective (COX-2) inhibitor, has been associated with an elevated risk of serious cardiovascular events, including and , due to its mechanism of preferentially inhibiting synthesis—a vasodilatory and anti-thrombotic —while sparing thromboxane A2 production from platelet COX-1, thereby promoting a prothrombotic state. This class effect was observed across COX-2 inhibitors, but valdecoxib's risks were substantiated in specific clinical settings. Two placebo-controlled, randomized trials in patients undergoing coronary artery bypass graft (CABG) surgery—the first evaluating followed by valdecoxib for postoperative pain (n=1,027) and the second assessing valdecoxib alone (n=933)—demonstrated a doubled incidence of cardiovascular events with valdecoxib regimens compared to . In a combined analysis of these trials, the for major cardiovascular events (, , or cardiovascular death) was 2.3 (95% CI: 1.1–4.7), with valdecoxib showing a threefold higher risk relative to . These events occurred early, often within 10–14 days of initiation, particularly in high-risk postoperative patients. Broader post-marketing data and regulatory reviews reinforced these findings, prompting the U.S. (FDA) to request voluntary withdrawal of valdecoxib on April 7, 2005, citing an unfavorable risk-benefit profile driven by cardiovascular thrombotic events, especially in vulnerable populations. Unlike nonselective NSAIDs, valdecoxib's selectivity amplified this hazard without offsetting gastrointestinal benefits sufficient to justify continued use in most patients. Subsequent analyses confirmed that COX-2 inhibitors like valdecoxib increased major vascular events by approximately 40–50% versus comparators, underscoring dose- and duration-dependent risks evident within weeks of treatment.

Dermatological and Other Adverse Effects

Valdecoxib was associated with a higher reported rate of serious cutaneous adverse reactions compared to other COX-2 selective inhibitors, including , Stevens-Johnson syndrome, , and exfoliative dermatitis. These reactions contributed significantly to the drug's risk profile, with data indicating valdecoxib had the highest percentage of Stevens-Johnson syndrome cases among monitored drugs in certain analyses. Clinical reports described severe allergic eruptions, sometimes presenting as hypersensitivity with fever, rash, and internal organ involvement, distinct in from classic Stevens-Johnson syndrome or patterns. The product labeling warned of potential for pruritus, rash, , or mucosal lesions progressing to life-threatening dermatologic events, prompting recommendations for immediate discontinuation upon skin reaction onset. Beyond dermatological effects, valdecoxib carried risks of reactions, including anaphylactic reactions and , reported in post-marketing surveillance. Rare but serious non-cutaneous adverse events encompassed , with symptoms like severe , neck stiffness, and altered mental status, potentially linked to sulfonamide moiety in susceptible individuals. Fluid retention, , and exacerbations were also noted, consistent with NSAID class effects but monitored closely due to overlap with cardiovascular concerns. Hepatic enzyme elevations occurred infrequently, though without widespread progression to severe in clinical data. Overall, these effects underscored valdecoxib's unfavorable benefit-risk balance, leading to its market withdrawal in 2005 alongside cardiovascular risks.

Development and Regulatory Timeline

Pre-Approval Development and FDA Approval

Valdecoxib, chemically known as SC-65872, was developed by Pharmacia Corporation as a selective (COX-2) inhibitor aimed at reducing and with minimized gastrointestinal side effects compared to non-selective non-steroidal drugs (NSAIDs). Pre-clinical studies demonstrated its high selectivity for COX-2 over COX-1, with an COX-2/COX-1 selectivity ratio exceeding 28,000, supporting its potential for and efficacy without significant inhibition of synthesis in the . Clinical development involved phase III trials evaluating valdecoxib's efficacy in (OA), (RA), primary , and acute pain, including dental surgery and post-operative models. In OA and RA trials, daily doses of 10 mg showed comparable pain relief and functional improvement to naproxen 500 mg twice daily, with lower incidences of endoscopic gastroduodenal ulcers (0.6% vs. 5.4% for naproxen). Acute pain studies supported dosing up to 40 mg for short-term use, demonstrating rapid onset and efficacy similar to traditional NSAIDs like ibuprofen. filed a (NDA 21-341) with the U.S. (FDA) on March 26, 2001, encompassing data from over 5,000 patients in arthritis trials and additional analgesic studies. The FDA's review process included assessments of chemistry, , biopharmaceutics, clinical , and , confirming valdecoxib's pharmacokinetic profile—characterized by rapid absorption, high (83%), and a of about 11 hours—with no major concerns beyond and substrates at therapeutic doses. Approval was granted on November 16, 2001, for relief of signs and symptoms of OA and adult RA (10 mg daily), primary (20 mg twice daily), and acute pain (20-40 mg daily for up to 7-10 days), marketed as Bextra by G.D. Searle & Co., a subsidiary. At approval, cardiovascular risks were not flagged as a barrier, with pre-approval data showing no excess thrombotic events relative to comparators, though long-term data remained limited to durations of up to 12 months.

Post-Marketing Surveillance and 2005 Withdrawal

Following its approval by the U.S. (FDA) in November 2001 for and , and subsequent expansions, valdecoxib underwent post-marketing surveillance primarily through the FDA's Reporting System (FAERS) and voluntary reports from healthcare providers and patients. This surveillance revealed an elevated risk of (SCARs), including Stevens-Johnson syndrome and , with post-approval reports exceeding pre-approval expectations; for instance, between 2001 and 2005, multiple cases were linked to valdecoxib, some fatal, prompting class-wide warnings for COX-2 inhibitors. These dermatological events occurred at higher rates than with traditional NSAIDs, particularly in patients receiving higher doses or with during perioperative settings. Cardiovascular safety signals also emerged in post-marketing data, building on class effects observed after rofecoxib's withdrawal in September 2004. Analysis of aggregated COX-2 inhibitor trials, including valdecoxib-specific studies like the Adenoma Prevention with Valdecoxib (APEX) trial, indicated a dose-dependent increase in thrombotic events such as and , with relative risks estimated at 1.3 to 2.0 compared to placebo or non-selective NSAIDs in long-term use. The FDA's review concluded that valdecoxib's cardiovascular hazard, combined with its existing for such risks, outweighed benefits, especially given comparable efficacy to alternatives with potentially lower profiles. On April 7, 2005, the FDA notified that valdecoxib's overall risk-benefit profile was unfavorable, requesting voluntary withdrawal from the U.S. market; acceded the same day, suspending sales and distribution worldwide to prioritize . This action followed an advisory committee review highlighting insufficient mitigation of identified risks through labeling alone, amid heightened scrutiny post-rofecoxib. Post-withdrawal, global regulatory bodies like the aligned, suspending authorizations and emphasizing the role of real-world data in uncovering rare but severe events underpowered in pre-approval trials.

Off-Label Promotion Settlement

In September 2009, Inc. agreed to a $2.3 billion settlement with the U.S. Department of Justice to resolve criminal and civil allegations of illegal off-label promotion of multiple drugs, including valdecoxib (marketed as Bextra), marking the largest healthcare fraud settlement in U.S. at the time. The allegations centered on 's promotion of Bextra for unapproved uses such as acute pain, surgical pain, and , as well as for dosages exceeding FDA-approved limits, between 2001 and 2005. A subsidiary, Pharmacia & Upjohn Company Inc., entered a guilty plea to a violation of the , Drug, and Cosmetic Act for misbranding Bextra with intent to defraud or mislead, resulting in a $1 billion criminal fine, offset partially by a $1.3 billion civil recovery under the False Claims Act for inducements to healthcare providers. The off-label promotion involved tactics such as paying kickbacks to doctors through speaker fees, honoraria, and sham consulting arrangements to encourage prescribing Bextra for non-indicated conditions, as well as funding purportedly independent educational programs that emphasized unapproved uses. sales representatives were trained to highlight Bextra's advantages over competitors for off-label applications, including post-surgical pain relief not covered by its label for and . These practices allegedly led to fraudulent claims submitted to federal healthcare programs like Medicare and , prompting whistleblower lawsuits under the False Claims Act that were later joined by the government. As part of the resolution, entered into a corporate integrity agreement with the Office of Inspector General, mandating enhanced compliance monitoring, reporting of off-label promotions, and oversight of interactions with healthcare professionals for five years. The settlement did not admit liability for all claims but resolved investigations stemming from Bextra's aggressive prior to its voluntary withdrawal from the market in April 2005 due to cardiovascular and skin reaction risks. State attorneys general also secured additional recoveries, with individual states receiving portions of the civil penalties based on expenditures affected by the off-label prescriptions.

Market Withdrawal Consequences

The voluntary withdrawal of valdecoxib (marketed as Bextra) from the U.S. and global markets on April 7, 2005, resulted in substantial revenue losses for , with the drug generating approximately $1.3 billion in sales the previous year, representing a significant portion of the company's COX-2 inhibitor portfolio alongside celecoxib (Celebrex). Analysts estimated a direct hit of around $400–550 million in projected 2005 U.S. revenues alone, contributing to a downward revision in 's full-year earnings forecast by approximately 3%, from an initial projection toward $14.7 billion in income. This loss exacerbated existing pressures from expirations on other blockbusters, though ratings agencies like Fitch maintained that the impact on 's overall was limited in the near term. In the broader pharmaceutical market, the withdrawal accelerated a decline in COX-2 inhibitor utilization, prompting shifts toward non-selective NSAIDs and increased co-prescription of inhibitors (PPIs) for gastroprotection, as evidenced by significant post-withdrawal prescription increases in these categories. This transition potentially elevated gastrointestinal risks for patients previously on valdecoxib for its purported GI-sparing profile, though empirical data on long-term patient outcomes remained mixed amid heightened scrutiny of class-wide cardiovascular hazards. Legally, the withdrawal fueled a wave of and consumer fraud lawsuits against , culminating in a $894 million settlement in October 2008 to resolve claims related to Bextra's risks, separate from prior off-label promotion penalties. These actions underscored regulatory pressures, with the FDA's determination of an unfavorable risk-benefit ratio for valdecoxib influencing subsequent post-marketing reforms, though direct causal links to systemic FDA policy shifts were more prominently tied to contemporaneous (Vioxx) events.

Post-Withdrawal Analysis

Ongoing Research and Class Comparisons

Post-withdrawal analyses of valdecoxib have primarily involved evaluations of its cardiovascular and dermatological risks within the broader COX-2 inhibitor class, confirming a dose-dependent increase in thrombotic events comparable to and high-dose celecoxib. No active clinical trials have been conducted since its 2005 market removal, as regulatory bodies deemed its risk-benefit profile unfavorable due to elevated incidences of , , and severe skin reactions like Stevens-Johnson syndrome and . Preclinical studies have explored potential repurposing, including induction of in MCF-7 cells and modulation of receptors for analgesia and , though these remain investigational without translation to human applications. In comparisons to other selective COX-2 inhibitors, valdecoxib exhibited similar efficacy to for acute postsurgical pain, achieving equivalent time-weighted pain relief over 6 hours but with faster onset at a 40 mg dose versus rofecoxib 50 mg. Its high COX-2 selectivity mirrored that of and celecoxib, conferring gastrointestinal benefits such as reduced ulcer complications (e.g., akin to celecoxib's 0.76 events per 100 patient-years versus ibuprofen's 1.45 in the CLASS trial), but without offsetting the class-wide prothrombotic effects. Valdecoxib's cardiovascular hazard was notably elevated in perioperative contexts, with a of 3.7 (95% CI 1.0–13.5) for adverse events following intravenous transition to oral valdecoxib 20 mg twice daily post-coronary artery bypass grafting, exceeding rofecoxib's 1.92 at 25 mg daily and celecoxib's 2.5–3.4 at 400–800 mg doses. Unlike celecoxib, which persists on markets with low-dose restrictions (≤200 mg/day) for and , valdecoxib's withdrawal stemmed from compounded dermatological risks absent or less pronounced in competitors, rendering its profile less favorable despite shared class mechanisms.
COX-2 InhibitorRegimen/ContextHazard Ratio for CV Events (95% CI)Reference
Valdecoxib20 mg BID post-CABG3.7 (1.0–13.5)
Rofecoxib25 mg/day (APPROVe trial)1.92
Celecoxib400 mg/day (APC trial)2.5

Debates on Risk-Benefit Balance

The U.S. (FDA) concluded in April 2005 that valdecoxib's overall benefit-risk profile was unfavorable, citing a twofold increase in serious cardiovascular events—such as and —observed in short-term placebo-controlled trials involving post-coronary artery bypass graft (CABG) patients, alongside a higher incidence of life-threatening skin reactions like Stevens-Johnson syndrome and , which resulted in at least seven reported deaths. Unlike some other COX-2 inhibitors, valdecoxib demonstrated no superior efficacy or gastrointestinal safety advantages over traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) in available data, rendering its added risks unjustifiable without offsetting benefits. Critics of the withdrawal decision have argued that the cardiovascular risks associated with valdecoxib, while evident in high-risk post-CABG populations, reflect a broader class effect of COX-2 inhibitors that is comparable to or only marginally higher than risks from tNSAIDs like or ibuprofen, with odds ratios for ranging from 1.24 to 1.55 for tNSAIDs versus 1.32 for as a COX-2 inhibitor. Proponents of this view emphasize valdecoxib's demonstrated reduction in serious gastrointestinal complications—such as ulcers and bleeding—relative to tNSAIDs, suggesting a potential net benefit for patients at high risk of gastrointestinal events but low cardiovascular risk, where short-term use could prioritize pain relief and without exceeding baseline NSAID hazards. However, post-withdrawal analyses have largely reinforced the FDA's position, noting valdecoxib's uniquely elevated skin reaction profile compared to other COX-2 agents like celecoxib, which remained available with restrictions, and the absence of long-term data supporting superior outcomes in general or populations. Ongoing research into NSAID class effects underscores that no agent is free of cardiovascular concerns, but valdecoxib's potency as a COX-2 inhibitor—potentially exacerbating prostacyclin-thromboxane imbalance—combined with its lack of differentiating advantages, has precluded rehabilitation efforts or comparative re-evaluations favoring its return. This has shifted clinical debates toward patient-specific risk stratification for remaining options, with indicating that benefits accrue primarily in contexts where gastrointestinal protection outweighs modest cardiovascular increments, a threshold valdecoxib failed to meet even pre-withdrawal.

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