Am J Gastroenterol.
2005 May;100(5):1043-50.
Valdecoxib is associated with improved dyspepsia-related health
compared with nonspecific NSAIDs in patients with osteoarthritis or rheumatoid
arthritis.
Rabeneck L, Goldstein JL, Vu A, Mayne TJ, Rublee DA.
Division of Gastroenterology, Department of Medicine, University of
Toronto, Canada.
OBJECTIVES: Dyspepsia and related gastrointestinal (GI) symptoms are
commonly reported by patients taking nonspecific nonsteroidal anti-inflammatory
drugs (NSAIDs) and significantly impact treatment effectiveness, cost,
and quality of life. This study sought to evaluate dyspepsia-related health
in osteoarthritis (OA) and rheumatoid arthritis (RA) patients taking valdecoxib
compared with patients taking nonspecific NSAIDs. METHODS: Analysis of
two separate, double-blind, placebo-controlled studies: one in RA patients
randomized to placebo, valdecoxib (10 and 20 mg once daily [o.d.]) and
naproxen (500 mg twice daily [b.i.d.]); one in OA patients randomized
to placebo, valdecoxib (10 and 20 mg o.d.), diclofenac (75 mg b.i.d.),
or ibuprofen (800 mg three times daily [t.i.d.]). Study population comprised
patients with RA in flare or clinically documented OA who required chronic
symptomatic treatment with NSAIDs/analgesics. Dyspepsia-related health
was evaluated at baseline and weeks 2, 6, and 12 (or early termination)
using the validated Severity of Dyspepsia Assessment (SODA) questionnaire.
This patient self-report tool consists of scales for evaluating dyspepsia
pain intensity, nonpain symptoms, and satisfaction. Analysis was based
on the intent-to-treat population with the last observation carried forward.
RESULTS: Valdecoxib was significantly better at endpoint than standard
doses of naproxen, diclofenac, and ibuprofen for pain intensity scores
(p < 0.05), and provided significantly improved nonpain symptom and
satisfaction scores compared with naproxen for patients with RA (p <
0.05). For RA patients, the difference between valdecoxib and naproxen
pain intensity scores were clinically meaningful; at all the time points,
significantly fewer patients receiving valdecoxib reported severe dyspepsia
pain intensity increases (>/=10 points) than those receiving naproxen.
At 12 wk, fewer patients receiving valdecoxib reported severe dyspepsia
pain intensity increases versus those receiving ibuprofen and diclofenac.
CONCLUSIONS: The GI tolerability of valdecoxib is superior to that of
nonspecific NSAIDs, and therefore can potentially have a favorable impact
on patient quality of life.
Expert Rev Neurother. 2005 Jan;5(1):11-24.
Valdecoxib for the management of chronic and acute pain.
Joshi GP.
Department of Anesthesiology and Pain Management, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9068,
USA. girish.joshi@utsouthwestern.edu
Cyclooxygenase-2 specific inhibitors have anti-inflammatory and analgesic
properties, and are effective in managing a wide range of chronic and
acute painful conditions such as adult rheumatoid arthritis, osteoarthritis,
migraine, primary dysmenorrhea and postoperative pain. Valdecoxib, an
orally administered cyclooxygenase-2 specific inhibitor, provides effective
pain relief for both chronic and acute conditions, and reduces postoperative
opioid use, with a concomitant reduction in opioid-related adverse events.
Valdecoxib also has superior gastrointestinal safety compared with nonspecific
nonsteroidal anti-inflammatory drugs, and at therapeutic doses, it is
generally safe and well tolerated in terms of renal and cardiovascular
events. This drug profile reviews the efficacy, safety and tolerability
of valdecoxib for the management of chronic and acute pain.
Eur J Clin Pharmacol. 2005 May 11;
The effect of mild and moderate hepatic impairment on the pharmacokinetics
of valdecoxib, a selective COX-2 inhibitor.
Sarapa N, Britto MR, Mainka MB, Parivar K.
Pfizer Global Research & Development, Clinical PK/PD, 10777 Science
Center Drive (Blg. 95), San Diego, CA, 92130, USA, nenad.sarapa@pfizer.com.
PURPOSE: This study evaluated the effects of varying degrees of hepatic
impairment on the pharmacokinetics and safety of valdecoxib following
single and multiple dosing.METHODS: This was an open-label, randomised,
parallel group study in 12 subjects with mild hepatic impairment (Child-Pugh
Class A) and in 13 with moderate hepatic impairment (Child-Pugh Class
B) matched for age, weight, sex, and smoking status; there were two control
groups of 12 healthy volunteers, one for each study group. All subjects
received a single dose of valdecoxib 20 mg on day 1 and valdecoxib 20
mg twice daily on days 4-7, followed by a single morning dose on day 8.
Plasma concentrations of free (unbound) and total valdecoxib and its active
hydroxylated metabolite (SC-66905) were measured following single and
multiple dosing (day 1 and day 8). Additionally, all subjects received
a single intravenous dose of lidocaine 60 mg during the pretreatment period
to determine plasma concentrations of monoethylglycinexylidide (MEGX)
as a marker of hepatic CYP3A4 activity.RESULTS: The mean apparent oral
clearance of free valdecoxib in plasma at steady state decreased by 22-25%
in those with mild to moderate impairment (corresponding to a 28-33% increase
in the AUC of free valdecoxib and a 19-23% decrease in the AUC of total
SC-66905). The mean free fraction of valdecoxib in plasma increased by
9-38%, resulting in a mean decrease in apparent oral clearance of total
valdecoxib in plasma of 0-15% (corresponding to a 0-17% increase in the
AUC of total valdecoxib). Individual AUCs for free valdecoxib and total
SC-66905 did not correlate well with AUCs for MEGX, indicating that decreases
in intrinsic clearance of valdecoxib in those with hepatic impairment
could not solely be explained by decreased CYP3A4 expression in hepatic
impairment.CONCLUSIONS: In our small study sample, mild and moderate hepatic
impairment appeared to have only a modest effect on valdecoxib and SC-66905
pharmacokinetics. The adjustment of valdecoxib dose or dosing regimen
does not appear mandatory in subjects with mild or moderate hepatic impairment,
although caution is necessary during treatment of these patients with
valdecoxib.
J Gen Intern Med. 2005 Jan;20(1):62-7.
Valdecoxib for treatment of primary dysmenorrhea. A randomized,
double-blind comparison with placebo and naproxen.
Daniels SE, Torri S, Desjardins PJ.
Scirex Corporation, 3200 Red River, Suite 300, Austin, TX 78705,
USA. SDaniels@Scirex.com
OBJECTIVE: To compare the analgesic efficacy of valdecoxib with placebo and naproxen sodium for relieving menstrual cramping and pain due to primary dysmenorrhea. DESIGN: Single-center, double-blind study with a 4-period, 4-sequence crossover design. Patients assessed pain intensity and pain relief at regular intervals up to 12 hours following the initial dose. SETTING: Privately owned outpatient clinic. PATIENTS/PARTICIPANTS: One hundred twenty patients with moderate to severe menstrual cramping were randomized. Eighty-seven patients completed all treatment cycles. INTERVENTIONS: Valdecoxib 20 mg or 40 mg, naproxen sodium 550 mg, or placebo twice a day as required for < or =3 days in a single menstrual cycle. MEASUREMENTS AND MAIN RESULTs: Both doses of valdecoxib (20 and 40 mg) were comparable to naproxen sodium and superior to placebo at all time points assessed for each of the primary end points. Valdecoxib and naproxen sodium had comparable onset and duration of action. Although the study design allowed patients 2 doses per day, only 15% and 20% of patients in the valdecoxib 20 mg and valdecoxib 40 mg groups, respectively, required remedication within the first 12 hours. The incidence of adverse events was similar between active and placebo groups. CONCLUSION: Valdecoxib provided a fast onset of analgesic action, a level of efficacy similar to naproxen sodium, and a high level of patient satisfaction in the relief of menstrual pain due to primary dysmenorrhea. Valdecoxib was effective and well tolerated and thus appears to be a viable treatment for menstrual pain due to primary dysmenorrhea.
Drug Dev Ind Pharm. 2005 Jan;31(1):1-10.
Enhancement of dissolution rate of valdecoxib using solid dispersions
with polyethylene glycol 4000.
Liu C, Liu C, Desai KG.
Life Science College, Ocean University of China, Qingdao, China.
The aim of the present study was to enhance the dissolution rate of valdecoxib
using its solid dispersions (SDs) with polyethylene glycol (PEG) 4000.
The phase solubility behavior of valdecoxib in the presence of various
concentrations of PEG 4000 in water was obtained at 37 degrees C. The
solubility of valdecoxib increased with increasing amount of PEG 4000
in water. Gibbs free energy (deltaG(zero)tr) values were all negative,
indicating the spontaneous nature of valdecoxib solubilization, and they
decreased with increase in the PEG 4000 concentration, demonstrating that
the reaction conditions became more favorable as the concentration of
PEG 4000 increased. The SDs of valdecoxib with PEG 4000 were prepared
at 1:1, 1:2, 1:5, and 1:10 (valdecoxib: PEG 4000) ratio by melting method.
Evaluation of the properties of the SDs was performed by using dissolution,
Fourier-transform infrared (FTIR) spectroscopy, differential scanning
calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy
(SEM) studies. The SDs of valdecoxib with PEG 4000 exhibited enhanced
dissolution rate of valdecoxib, and the rate increased with increasing
concentration of PEG 4000 in SDs. Mean dissolution time (MDT) of valdecoxib
decreased significantly after preparation of SDs and physical mixture
with PEG 4000. The FTIR spectroscopic studies showed the stability of
valdecoxib and absence of well-defined valdecoxib-PEG 4000 interaction.
The DSC and XRD studies indicated the amorphous state of valdecoxib in
SDs of valdecoxib with PEG 4000. The SEM pictures showed the formation
of effective SDs of valdecoxib with PEG 4000, since well-defined changes
in the surface nature of valdecoxib, SDs, and physical mixture were observed.
Clin Ther. 2004 Aug;26(8):1249-60.
Effects of valdecoxib in the treatment of chronic low back pain:
results of a randomized, placebo-controlled trial.
Coats TL, Borenstein DG, Nangia NK, Brown MT.
Benchmark Research, Austin, Texas 78705, USA. annrutledge@benchmarkresearch.net
BACKGROUND: Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor,
is indicated for relief of the signs and symptoms of rheumatoid arthritis,
osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific
inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory
drugs in reducing inflammatory pain while sparing the gastrointestinal
and platelet toxicity associated with nonspecific COX-1 inhibition. OBJECTIVE:
The aim of this study was to assess the analgesic efficacy and tolerability
of valdecoxib 40 mg/d compared with placebo in the treatment of chronic
low back pain. METHODS: This 4-week, prospective, randomized, double-blind
placebo-controlled, parallel-group study was conducted at 37 centers across
the United States and 5 centers in Canada. Patients aged > or =18 years
with chronic low back pain in flare were enrolled. Patients were randomized
to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks.
Patients rated low back pain intensity on a visual analog scale and completed
the Roland-Morris Disability Questionnaire and the modified Brief Pain
Inventory-Short Form (mBPI-SF) at each visit. RESULTS: Two hundred ninety-three
patients were enrolled. The valdecoxib group comprised 148 patients (81
women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight,
86.6 [20.9] kg), and the placebo group included 145 patients (85 women,
60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6
[19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients
(91%) who received valdecoxib and 115 patients (79%) who received placebo.
No statistically significant differences in patient baseline characteristics
were noted between treatment groups, except in response to 1 mBPI-SF question;
patients in the valdecoxib group reported significantly greater interference
in relations with other people due to pain than did those in the placebo
group (P = 0.048). Changes from baseline in low back pain intensity were
significantly greater in valdecoxib-treated patients at each assessment
(all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly
greater pain relief with valdecoxib at each assessment (all, P < or
= 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire
score with valdecoxib were significantly greater than with placebo at
each assessment (all, P < or = 0.003). Although the overall incidence
of adverse events (AEs) was significantly higher among patients receiving
valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively;
P = 0.042), no significant differences were found between groups for the
incidence of any individual AE. Most AEs (89% [77/87 total events]) were
mild or moderate in severity. CONCLUSIONS: In this study of patients with
chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within
1 week) and consistent relief (over 4 weeks). In addition, significant
improvement in function and decreased disability were found with valdecoxib
compared with placebo.
Bioorg Med Chem Lett. 2004 Dec 20;14(24):6001-6.
Carbonic anhydrase inhibitors. Inhibition of the prokariotic beta
and gamma-class enzymes from Archaea with sulfonamides.
Zimmerman S, Innocenti A, Casini A, Ferry JG, Scozzafava A, Supuran
CT.
Department of Biochemistry and Molecular Biology, Eberly College of
Science, Pennsylvania State University, University Park, PA 16802-4500,
USA.
A detailed inhibition study of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the beta- and gamma-families from Archaea with sulfonamides has been performed. Compounds included in this study were the clinically used sulfonamide CA inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, valdecoxib, celecoxib, dorzolamide, sulfanilamide, dichlorophanamide, as well as sulfanilamide analogs, halogenated sulfanilamides, and some 1,3-benzenedisulfonamide derivatives. The two gamma-CAs from Methanosarcina thermophila (Zn-Cam and Co-Cam) showed very different inhibitory properties with these compounds, as compared to the alpha-CA isozymes hCA I, II, and IX, and the beta-CA from Methanobacterium thermoautotrophicum (Cab). The best Zn-Cam inhibitors were sulfamic acid and acetazolamide, with inhibition constants in the range of 63-96nM, whereas other investigated aromatic/heterocylic sulfonamides showed a rather levelled behavior, with K(I)s in the range of 0.12-1.70muM. The best Co-Cam inhibitors were topiramate and p-aminoethyl-benzenesulfonamide, with K(I)s in the range of 0.12-0.13muM, whereas the worst one was homosulfanilamide (K(I) of 8.50muM). In the case of Cab, the inhibitory power of these compounds varied to a much larger extent, with sulfamic acid and sulfamide showing millimolar affinities (K(I)s in the range of 44-103mM), whereas the best inhibitor was ethoxzolamide, with a K(I) of 5.35muM. Most of these sulfonamides showed inhibition constants in the range of 12-100muM against Cab. Thus, the three CA families investigated up to now possess a very diverse affinity for sulfonamides, the inhibitors with important medicinal, and environmental applications.
J Pharmacol Exp Ther. 2004 Oct 19.
Valdecoxib: Assessment of COX-2 potency and selectivity.
Gierse JK, Zhang Y, Hood WF, Walker MC, Trigg JS, Maziasz
TJ, Koboldt CM, Muhammad JL, Zweifel BS, Masferrer JL, Isakson PC, Seibert
K.
Pfizer.
The discovery of a second isoform of cyclooxygenase (COX) led to the
search for compounds that could selectively inhibit COX-2 in humans, while
sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were
among the molecules developed from these efforts. We report here the pharmacological
properties of a third selective COX-2 inhibitor, valdecoxib, which is
the most potent and in vitro selective of the marketed COX-2 inhibitors
that we have studied. Recombinant human COX-1 and COX-2 were used to screen
for new highly potent and in vitro selective COX-2 inhibitors and compare
kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors.
Valdecoxib potently inhibits recombinant COX-2, with an IC50 of 0.005
microM; this compares with IC50 values of 0.05 microM for celecoxib, 0.5
microM for rofecoxib and 2.1 microM for etoricoxib. Unique binding interactions
of valdecoxib with COX-2 translate into a fast rate of inactivation of
COX-2 110,000 M-1 sec-1 (compared to 7,000 M-1 sec-1 for rofecoxib and
80 M-1 sec-1 for etoricoxib). The overall saturation binding affinity
for COX-2 of valdecoxib is 2.6 nM (compared to 1.6 nM for celecoxib, 51
nM for rofecoxib and 260 nM for etoricoxib), with a slow off rate (t1/2
~ 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at
very high concentrations (IC50 = 150 uM). Collectively, these data provide
a mechanistic basis for the potency and in vitro selectivity of valdecoxib
for COX-2. Valdecoxib showed similar activity in the human whole blood
COX assay (COX-2 IC50 = 0.24 uM; COX-1 IC50 = 21.9 uM). We also determined
whether this in vitro potency and selectivity translated to significant
potency in vivo. In rats valdecoxib demonstrated marked potency in acute
and chronic models of inflammation (air pouch ED50 = 0.06 mg/kg; paw edema
ED50 = 5.9 mg/kg; adjuvant arthritis ED50 = 0.03 mg/kg). In these same
animals, COX-1 was spared at doses greater than 200 mg/kg. These data
provide a basis for the observed potent anti-inflammatory activity of
valdecoxib in humans.
Clin Ther. 2004 Aug;26(8):1249-60.
Effects of valdecoxib in the treatment of chronic low back pain:
results of a randomized, placebo-controlled trial.
Coats TL, Borenstein DG, Nangia NK, Brown MT.
Benchmark Research, Austin, Texas 78705, USA.
BACKGROUND: Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic doses of COX-2 specific inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs in reducing inflammatory pain while sparing the gastrointestinal and platelet toxicity associated with nonspecific COX-1 inhibition. OBJECTIVE: The aim of this study was to assess the analgesic efficacy and tolerability of valdecoxib 40 mg/d compared with placebo in the treatment of chronic low back pain. METHODS: This 4-week, prospective, randomized, double-blind placebo-controlled, parallel-group study was conducted at 37 centers across the United States and 5 centers in Canada. Patients aged > or =18 years with chronic low back pain in flare were enrolled. Patients were randomized to receive valdecoxib 40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated low back pain intensity on a visual analog scale and completed the Roland-Morris Disability Questionnaire and the modified Brief Pain Inventory-Short Form (mBPI-SF) at each visit. RESULTS: Two hundred ninety-three patients were enrolled. The valdecoxib group comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6 [13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the placebo group included 145 patients (85 women, 60 men; mean [SD] age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg). Of the enrolled patients, 249 completed the study: 134 patients (91%) who received valdecoxib and 115 patients (79%) who received placebo. No statistically significant differences in patient baseline characteristics were noted between treatment groups, except in response to 1 mBPI-SF question; patients in the valdecoxib group reported significantly greater interference in relations with other people due to pain than did those in the placebo group (P = 0.048). Changes from baseline in low back pain intensity were significantly greater in valdecoxib-treated patients at each assessment (all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated significantly greater pain relief with valdecoxib at each assessment (all, P < or = 0.014 vs placebo). Improvements in mean Roland-Morris Disability Questionnaire score with valdecoxib were significantly greater than with placebo at each assessment (all, P < or = 0.003). Although the overall incidence of adverse events (AEs) was significantly higher among patients receiving valdecoxib than those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042), no significant differences were found between groups for the incidence of any individual AE. Most AEs (89% [77/87 total events]) were mild or moderate in severity. CONCLUSIONS: In this study of patients with chronic low back pain, valdecoxib 40 mg/d provided rapid relief (within 1 week) and consistent relief (over 4 weeks). In addition, significant improvement in function and decreased disability were found with valdecoxib compared with placebo.
Pain. 2004 Oct;111(3):286-96.
Efficacy and safety of valdecoxib for treatment of osteoarthritis
and rheumatoid arthritis: systematic review of randomised controlled trials.
Edwards JE, McQuay HJ, Moore RA.
Nuffield Department of Anaesthetics, University of Oxford, Oxford
Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ, UK.
Our objective was to determine the efficacy and safety of valdecoxib
(a cyclo-oxygenase 2 inhibitor) in the treatment of arthritis. Randomised,
controlled trials comparing 10 or 20mg valdecoxib with placebo or non-steroidal
anti-inflammatory drugs (NSAIDs) in patients with active osteoarthritis
or rheumatoid arthritis. The manufacturer provided clinical trial reports.
Data were combined through meta-analysis. Main outcomes were patient global
rating of arthritis, arthritis pain, Western Ontario and McMaster Universities
indices for osteoarthritis, American College of Rheumatology indices for
rheumatoid arthritis, discontinuation, endoscopic ulcers, clinically significant
upper gastrointestinal or renal events. Nine trials (five in osteoarthritis,
four in rheumatoid arthritis) were included with 5726 patients. Overall,
valdecoxib 10 and 20mg were superior to placebo and equivalent in efficacy
to maximum daily doses of NSAIDs. Significantly fewer discontinuations
because of gastrointestinal adverse events (4% versus 8%), or endoscopic
ulcers of 3mm or more (5% versus 13%) occurred with valdecoxib compared
with NSAIDs. Clinically significant upper gastrointestinal events occurred
in 2/2733 (0.1%) with valdecoxib compared with 8/1846 (0.4%) with NSAIDs.
Rates of clinically significant renal events were the same (2-3%) for
valdecoxib and NSAIDs. At an appropriate dose valdecoxib was as effective
as NSAIDs in osteoarthritis and rheumatoid arthritis. There were fewer
gastrointestinal adverse event withdrawals and endoscopically detected
ulcers. Convincing evidence of reduced major gastrointestinal adverse
events could not be addressed by the trials.
Aliment Pharmacol Ther. 2004 Sep 1;20(5):527-38.
Reduced incidence of upper gastrointestinal ulcer complications
with the COX-2 selective inhibitor, valdecoxib.
Goldstein JL, Eisen GM, Agrawal N, Stenson WF, Kent JD, Verburg
KM.
University of Illinois at Chicago, Chicago, IL 60612, USA.
AIM: In a predefined analysis, data were pooled from eight blinded, randomized,
controlled trials, and separately from three long-term, open-label trials
to determine the rate of upper gastrointestinal ulcer complications with
the cyclo-oxygenase-2 selective inhibitor, valdecoxib, vs. non-selective
non-steroidal anti-inflammatory drugs. METHODS: In randomized, controlled
trials, 7434 osteoarthritis and rheumatoid arthritis patients received
placebo (n = 973), valdecoxib 5-80 mg daily (n = 4362), or a non-selective
non-steroidal anti-inflammatory drug (naproxen, ibuprofen or diclofenac;
n = 2099) for 12-26 weeks. In long-term, open-label trials, 2871 patients
received valdecoxib 10-80 mg daily for up to 1 year. All potential events
were reviewed by a blinded, independent review committee based on a priori
definitions of ulcer complications (perforations, obstructions, bleeds).
RESULTS: In randomized, controlled trials, 19 of 955 potential events
were adjudicated to be ulcer complications. Valdecoxib was associated
with a significantly lower ulcer complication rate than non-selective
non-steroidal anti-inflammatory drugs (0.68% vs. 1.96%, all patients;
0.29% vs. 2.08%, non-aspirin users; P < 0.05). In long-term, open-label
trials, seven of 310 potential events were adjudicated to be ulcer complications;
the annualized incidence for valdecoxib was 0.39% (seven of 1791 patient-years)
for all patients and 0.2% (three of 1472 patient-years) for non-aspirin
users. CONCLUSIONS: Valdecoxib, including above recommended doses, is
associated with a significantly lower rate of upper gastrointestinal ulcer
complications than therapeutic doses of non-selective non-steroidal anti-inflammatory
drugs.
Am J Ther. 2004 Jul-Aug;11(4):244-50.
Effects of the cyclooxygenase-2 specific inhibitor valdecoxib
versus nonsteroidal antiinflammatory agents and placebo on cardiovascular
thrombotic events in patients with arthritis.
White WB, Strand V, Roberts R, Whelton A.
Division of Hypertension and Clinical Pharmacology, Department of
Medicine, University of Connecticut School of Medicine, 263 Farmington
Avenue, Farmington, CT 06030-3940, USA.
There have been concerns that the risk of cardiovascular thrombotic events
may be higher with cyclooxygenase (COX)-2-specific inhibitors than nonselective
nonsteroidal antiinflammatory drugs (NSAIDs). We evaluated cardiovascular
event data for valdecoxib, a new COX-2-specific inhibitor in approximately
8000 patients with osteoarthritis and rheumatoid arthritis treated with
this agent in randomized clinical trials. The incidence of cardiovascular
thrombotic events (cardiac, cerebrovascular and peripheral vascular, or
arterial thrombotic) was determined by analyzing pooled valdecoxib (10-80
mg daily), nonselective NSAID (diclofenac 75 mg bid, ibuprofen 800 mg
tid, or naproxen 500 mg bid) and placebo data from 10 randomized osteoarthritis
and rheumatoid arthritis trials that were 6-52 weeks in duration. The
incidence rates of events were determined in all patients (n = 7934) and
in users of low-dose (< or =325 mg daily) aspirin (n = 1051) and nonusers
of aspirin (n = 6883). Crude and exposure-adjusted incidences of thrombotic
events were similar for valdecoxib, NSAIDs, and placebo. The risk of serious
thrombotic events was also similar for each valdecoxib dose. Thrombotic
risk was consistently higher for users of aspirin users than nonusers
of aspirin (placebo, 1.4% vs. 0%; valdecoxib, 1.7% vs. 0.2%; NSAIDs, 1.9%
vs. 0.5%). The rates of events in users of aspirin were similar for all
3 treatment groups and across valdecoxib doses. Short- and intermediate-term
treatment with therapeutic (10 or 20 mg daily) and supratherapeutic (40
or 80 mg daily) valdecoxib doses was not associated with an increased
incidence of thrombotic events relative to nonselective NSAIDs or placebo
in osteoarthritis and rheumatoid arthritis patients in controlled clinical
trials.
J Indian Med Assoc. 2003 Dec;101(12):764, 766, 727.
Evaluation of the efficacy, safety and tolerability of valdecoxib
gel (1%) in adult patients with painful inflammatory joint disease.
Jagtap SA, Chincholi S, Taneja PK, Ismail ND, Ram S, Sarvagod
SB, Dongre N, Desai A.
Sir JJ Group of Hospitals and Grant Medical College, Mumbai 400008.
Valdecoxib, a COX-2 inhibitor, has recently been introduced as a gel formulation. The present study was conducted to evaluate the efficacy, safety and tolerability of valdecoxib gel in adult patients with painful inflammatory joint conditions. The present study was a 10-day prospective, open, multicentric (6 centres) trial. Patients with clinical and radiological diagnosis of painful inflammatory joint conditions were treated with valdecoxib gel (1%). Efficacy was assessed by visual analogue scale (VAS), patient's and physician's global assessment of pain relief. Grading of associated clinical manifestations such as stiffness, swelling, tenderness and restriction of mobility was done. Tolerability and safety was assessed by physical examination, laboratory parameters and evaluation of adverse events. There was a statistically significant decrease in the mean pain visual analogue score (p<0.05). Onset of pain relief was within 15 minutes. There was a reduction of 58.8%, 57.2%, 65.4% and 60.2% in mean scores of stiffness, swelling, tenderness and mobility respectively from the baseline which was statistically significant. The laboratory values were within normal limits. The drug was well tolerated. There was no report of any hypersensitivity reaction. This study confirms that valdecoxib gel (1%) is an effective and safe option for the management of painful inflammatory joint conditions.
Rev Med Liege. 2004 Apr;59(4):251-4.
[Valdecoxib (Bextra)]
[Article in French]
Scheen AJ, Malaise M.
Universite de Liege.
Valdecoxib (Bextra tablets of 10 mg and 20 mg) is a new non steroidal antiinflammatory drug (NSAID) that selectively inhibits COX-2 isoform of cyclo-oxygenase. It is indicated for the symptomatic treatment of osteoarthritis or rheumatoid arthritis (10 to 20 mg once a day) and for the treatment of primary dysmenorrhea (40 mg once a day). Valdecoxib is as efficacious as conventional non-COX-2 selective NSAIDs, but offers the advantage of a much better gastrointestinal tolerance. Valdecoxib has a prodrug that can be administered intravenously or intramuscularly (parecoxib, Dynastat) and has been developed for the short-term treatment of postsurgical pain.
Drugs. 2004;64(11):1231-61.
Valdecoxib: a review of its use in the management of osteoarthritis,
rheumatoid arthritis, dysmenorrhoea and acute pain.
Fenton C, Keating GM, Wagstaff AJ.
Adis International Limited, Auckland, New Zealand.
Valdecoxib is an orally administered, highly selective cyclo-oxygenase
(COX)-2 inhibitor with anti-inflammatory and analgesic properties. In
well designed trials, valdecoxib demonstrated efficacy versus placebo
in patients with osteoarthritis (OA), rheumatoid arthritis (RA), primary
dysmenorrhoea and postoperative pain. Initial results in patients with
migraine headache were promising. The efficacy of valdecoxib appears dose
dependent up to 40 mg/day. Valdecoxib 10 mg/day was as effective as naproxen
and rofecoxib in improving signs and symptoms of OA. The American College
of Rheumatology 20% response rate was similar in recipients of valdecoxib,
naproxen and diclofenac in patients with RA. In patients with dysmenorrhoea,
valdecoxib 20 or 40 mg up to twice daily provided as effective pain relief
as naproxen sodium 550 mg twice daily. In acute post-surgical pain, single-dose
valdecoxib 40 mg had a rapid onset of action, provided similar analgesia
to oxycodone 10 mg plus paracetamol (acetaminophen) 1000 mg and provided
a longer time to rescue medication than rofecoxib or oxycodone/paracetamol
after oral surgery. Pre-emptive administration of valdecoxib 10-80 mg
was particularly effective in dental pain. Valdecoxib had opioid-sparing
effects after hip or knee arthroplasty and reduced pain after laparoscopic
cholecystectomy. Valdecoxib is generally well tolerated. The incidence
of gastroduodenal ulcers was generally lower than with nonselective NSAIDs
(i.e. NSAIDs not specifically developed as selective COX-2 inhibitors).
With concomitant aspirin, the ulcer rate in valdecoxib recipients increased
significantly, but was still lower than that in recipients of aspirin
plus nonselective NSAIDs. In conclusion, valdecoxib, a COX-2-selective
inhibitor, is as efficacious in pain relief as nonselective NSAIDs, with
better gastrointestinal tolerability. It was as effective in RA, OA and
primary dysmenorrhoea (the approved indications) as nonselective NSAIDs
and as effective as rofecoxib in RA flare. In acute post-surgical pain,
valdecoxib provided similar pain relief to oxycodone/paracetamol, had
a long duration of action, a rapid onset of analgesia and was opioid-sparing.
Valdecoxib provides a valuable alternative in the treatment of chronic
arthritis pain and acute pain.
J Clin Pharmacol. 2003 Sep;43(9):974-82.
Valdecoxib, a COX-2-specific inhibitor, does not affect cardiac
repolarization.
Sarapa N, Britto MR, Cotton B, Cox SR, Francom SF, Jin N, Polasek
ED, Sainati SM, Crosby-Sessoms SL, Fleishaker JC.
Department of Clinical Pharmacology, Pharmacia Corporation, 5200 Old
Orchard Road, Skokie, IL 60077, USA.
This double-blind, four-way crossover study assessed the effect of valdecoxib on the QTc interval duration in 25 male and 9 female healthy adults. Subjects received placebo or 40 mg, 80 mg, or 120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained for 24 hours before the first treatment (baseline) and on the 5th day of each treatment. The study was statistically powered to detect a difference of > or = 5.6 ms in the average daily QTc change from baseline and a > or = 7.8-ms difference in the average maximal daily change from baseline. No QTc prolongation versus placebo (Fridericia's or Bazett's correction) was observed for any valdecoxib dose. A 22% greater than proportional increase in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose range, supporting the conclusiveness of the negative QTc risk assessment even at supratherapeutic doses (up to three times the maximum recommended dose of 40 mg per day) and concentrations. In conclusion, repeated administration of doses up to 120 mg valdecoxib had no effect on cardiac repolarization in healthy volunteers, suggesting that chronic administration of valdecoxib to patients would not increase the risk from cardiac arrhythmia associated with QT prolongation
Clin Ther. 2003 Mar;25(3):817-51.
Valdecoxib: a review.
Chavez ML, DeKorte CJ.
Pharmacy Practice Department, College of Pharmacy, Midwestern University-Glendale,
Glendale, Arizona 85308, USA.
BACKGROUND: Traditional nonsteroidal anti-inflammatory drugs (NSAIDs)
such as diclofenac, ibuprofen, naproxen, and related agents are nonselective
inhibitors of both cyclooxygenase-1 (COX-1) and COX-2, which catalyze
prostaglandin synthesis. This inhibition accounts not only for the analgesic,
anti-inflammatory, and antipyretic effects of these agents, but also for
side effects such as gastric mucosal damage and renal toxicity. Substantial
evidence suggests that sparing COX-1 is advantageous for gastric safety.
OBJECTIVE: This article reviews available information on the new COX-2-selective
inhibitor valdecoxib, including its clinical pharmacology, pharmacokinetics,
adverse effects, potential drug interactions, and contraindications and
warnings. Results of clinical trials of efficacy and tolerability are
summarized. METHODS: Articles for inclusion in this review were identified
through searches of PubMed and MEDLINE (1966-December 2002) and International
Pharmaceutical Abstracts (1970-December 2002). Search terms included valdecoxib,
Bextra, COX-2-selective inhibitors, coxibs, and selective cyclooxygenase
inhibitors. The reference lists of identified articles were reviewed for
additional publications. Product information was also obtained from the
manufacturer of valdecoxib. RESULTS: Fourteen clinical studies involving
> 4000 patients have been conducted. Valdecoxib was significantly more
effective than placebo in the treatment of adult rheumatoid arthritis,
osteoarthritis, pain associated with primary dysmenorrhea, and postoperative
pain. Valdecoxib was comparable to naproxen for the treatment of rheumatoid
arthritis in 1 study and equivalent to naproxen for the treatment of osteoarthritis
in other studies. Three studies found valdecoxib comparable to naproxen
sodium for the relief of moderate to severe pain due to primary dysmenorrhea,
and others found valdecoxib comparable to oxycodone plus acetaminophen
and significantly more effective than rofecoxib for the relief of pain
associated with dental surgery (P < 0.05). Four safety studies and
2 reviews of clinical trials documented lower rates of endoscopic gastroduodenal
ulcer formation with valdecoxib compared with ibuprofen, naproxen, and
diclofenac (P < 0.001 to P < 0.05). Valdecoxib did not inhibit platelet
function (bleeding time and platelet aggregation) in healthy adults or
in the elderly. Due to the risk of potentially serious skin and allergic
reactions, patients who are allergic to sulfa-containing drugs should
not take valdecoxib. The drug should be discontinued immediately if rash
develops. CONCLUSIONS: In clinical trials, valdecoxib was effective for
the treatment of osteoarthritis, rheumatoid arthritis, and moderate to
severe pain associated with primary dysmenorrhea. As with the other COX-2-selective
inhibitors (celecoxib and rofecoxib), valdecoxib appears to produce less
gastrointestinal toxicity than conventional nonselective NSAIDs, although
some of the relevant clinical studies have been published only as abstracts.
Use of valdecoxib should be reserved for patients at risk for NSAID-induced
gastrointestinal problems.
Aliment Pharmacol Ther. 2003 Jul 1;18(1):125-32.
A comparison of the upper gastrointestinal mucosal effects of
valdecoxib, naproxen and placebo in healthy elderly subjects.
Goldstein JL, Kivitz AJ, Verburg KM, Recker DP, Palmer RC, Kent
JD.
University of Illinois at Chicago, Chicago, IL 60612, USA.
BACKGROUND: In long-term outcomes studies, cyclooxygenase COX-2 specific
inhibitors spare COX-1 at supratherapeutic doses and therefore demonstrate
improved gastrointestinal safety over nonspecific nonsteroidal anti-inflammatory
drugs (NSAIDs). However, in clinical practice, anti-inflammatory drugs
are often used for short-term treatment of pain. AIM: To compare the short-term
upper gastrointestinal mucosal effects of naproxen with the new COX-2
specific inhibitor, valdecoxib, or placebo, in elderly subjects. METHODS:
In this multicentre, double-blind, randomized, study, elderly subjects
(65-76 years old), with a normal baseline esophagogastroduodenoscopy (EGD),
received oral valdecoxib (a supratherapeutic 40 mg b.d. dosage, n = 62),
naproxen (500 mg b.d., n = 62), or placebo (n = 62) for 6.5 days. Upper
gastrointestinal mucosal injury was evaluated post-treatment by EGD (day
7). RESULTS: Subjects receiving naproxen (11/60, 18%) had significantly
more gastroduodenal ulcers post-treatment than those receiving placebo
(2/61, 3%; P < 0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar
significant finding was observed for gastric ulcer rates. All treatments
had similar adverse event rates and clinical laboratory findings. CONCLUSIONS:
Valdecoxib, even at supratherapeutic doses, was associated with an ulcer
rate significantly lower than naproxen but similar to placebo in healthy
elderly subjects, despite the short duration of therapy (6.5 days). Naproxen
and valdecoxib were as well tolerated as placebo.
Rheumatology (Oxford). 2003 Oct;42(10):1207-15.
Valdecoxib is as effective as diclofenac in the management of
rheumatoid arthritis with a lower incidence of gastroduodenal ulcers:
results of a 26-week trial.
Pavelka K, Recker DP, Verburg KM.
Institute of Rheumatology, Prague, Czech Republic.
OBJECTIVE: To compare the efficacy and upper gastrointestinal (GI) safety of valdecoxib 20 and 40 mg daily with those of diclofenac 75 mg slow release (SR) twice daily in treating rheumatoid arthritis (RA). METHODS: Seven hundred and twenty-two patients with adult-onset RA were enrolled into this 26-week, randomized, multicentre, double-blind, parallel-group study (246 in the valdecoxib 20 mg daily arm, 237 in the valdecoxib 40 mg daily arm and 239 in the diclofenac 75 mg SR daily arm). Acetylsalicylic acid use (< or =325 mg per day) was similar across all groups: 5.4% in the diclofenac group, 5.7% in the valdecoxib 20 mg group and 5.9% in the valdecoxib 40 mg group. Efficacy was measured by the Patient's Assessment of Arthritis Pain [visual analogue scale (VAS)] and the modified Health Assessment Questionnaire (mHAQ) at baseline and at weeks 2, 6, 8, 12, 18 and 26 of treatment, or at early termination. Upper GI safety was evaluated by endoscopy at the end of treatment, which took place no more than 2 days after the last dose of study medication or at early termination. RESULTS: Valdecoxib 20 and 40 mg daily were comparable to diclofenac 75 mg SR twice daily in treating the signs and symptoms of RA. No significant differences were observed between treatment groups with respect to mean changes from baseline in the Patient's Assessment of Arthritis Pain (VAS) or mHAQ. The incidence of gastroduodenal ulcers in patients receiving valdecoxib 20 mg daily (6%) and valdecoxib 40 mg daily (4%) was significantly lower (P < 0.001) than in patients receiving diclofenac 75 mg SR twice daily (16%). Valdecoxib 20 mg daily was also associated with significantly improved GI tolerability (P = 0.035) compared with diclofenac. CONCLUSIONS: Single daily doses of valdecoxib 20 and 40 mg provided efficacy comparable to that of diclofenac, with a superior upper GI safety profile in the long-term treatment of RA patients.
