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CLINICAL PHARMACOLOGY
Mechanism of Action
Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID)
that exhibits anti-inflammatory,analgesic and antipyretic
properties in animal models.The mechanism of action is
believed to be due to inhibition of prostaglandin synthesis
primarily through inhibition of cyclooxygenase-2 (COX-2).At
therapeutic plasma concentrations in humans valdecoxib
does not inhibit cyclooxygenase-1 (COX-1).
Pharmacokinetics
Absorption
Valdecoxib achieves maximal plasma concentrations
in approximately 3 hours.The absolute bioavailability
of valdecoxib is 83% following oral administration of
BEXTRA compared to intravenous infusion of valdecoxib.
Dose proportionality was demonstrated after single doses
(1–400mg) of valdecoxib.With multiple doses (up
to 100 mg/day for 14 days),valdecoxib exposure as measured
by the AUC,increases in a more than proportional manner
at doses above 10 mg BID.Steady state plasma concentrations
of valdecoxib are achieved by day 4.
The steady state pharmacokinetic parameters of valdecoxib
in healthy male subjects are shown in Table1.
Table 1 : Mean
(SD) Steady State Pharmacokinetic Parameters
|
Steady
State Pharmacokinetic Parameters after Valdecoxib
10 mg Once Daily for 14 Days |
Healthy
Male Subjects (n=8,20 to 42 yr.) |
|
AUC(0-24hr)
(hr·ng/mL) |
1479.0
|
(291.9)
|
|
Cmax
(ng/mL) |
161.1
|
(48.1)
|
| Tmax
(hr) |
2.25
|
(0.71)
|
| Cmin
(ng/mL) |
21.9
|
(7.68)
|
| Elimination
Half-life (hr) |
8.11
|
(1.32)
|
No clinically significant age or gender differences were
seen in pharmacokinetic parameters that would require dosage
adjustments.
Effect of Food and Antacid
BEXTRA can be taken with or without food. Food
had no significant effect on either the peak plasma concentration
(Cmax) or extent of absorption (AUC) of valdecoxib when
BEXTRA was taken with a high fat meal. The time to peak
plasma concentration (Tmax), how-ever, was delayed by 1-2
hours. Administration of BEXTRA with antacid (aluminum/magnesium
hydroxide) had no significant effect on either the rate
or extent of absorption of valdecoxib.
Distribution
Plasma protein binding for valdecoxib is about 98% over
the concentration range (21-2384 ng/mL).Steady state apparent
volume of distribution (Vss/F) of valdecoxib is approximately
86 L after oral administration. Valdecoxib and its active
metabolite preferentially partition into erythrocytes with
a blood to plasma concentration ratio of about 2.5:1.This
ratio remains approximately constant with time and therapeutic
blood concentrations.
Metabolism
In humans, valdecoxib undergoes extensive hepatic metabolism
involving both P450 isoenzymes (3A4 and 2C9) and non-P450
dependent pathways (i.e., glucuronidation).Concomitant administration
of BEXTRA with known CYP 3A4 and 2C9 inhibitors (e.g., flu-conazole
and ketoconazole) can result in increased plasma exposure
of valdecoxib (see PRECAUTIONS—Drug Interactions).
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 less than 2% of the valdecoxib
dose excreted in the urine and feces. Due to its low concentration
in the systemic circulation,it is not likely to contribute
significantly to the efficacy profile of BEXTRA.
Excretion
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. The apparent oral clearance (CL/F) of valdecoxib
is about 6 L/hr. The mean elimination half-life (T1/2) ranges
from 8–11 hours, and increases with age.
Special Populations
Geriatric
In elderly subjects (>65 years),weight-adjusted steady
state plasma concentrations (AUC(0-12hr)) are about 30%
higher than in young subjects.No dose adjustment is needed
based on age.
Pediatric
BEXTRA has not been investigated in pediatric patients below
18years of age.
Race
Pharmacokinetic differences due to race have not been identified
in clinical and pharmacokinetic studies conducted to date.
Hepatic Insufficiency
Valdecoxib plasma concentrations are significantly increased
(130%) in patients with moderate (Child-Pugh Class B) hepatic
impairment. In clinical trials, doses of BEXTRA above those
recommended have been associated with fluid retention. Hence,
treatment with BEXTRA should be initiated with caution in
patients with mild to moderate hepatic impairment and fluid
retention. The use of BEXTRA in patients with severe hepatic
impairment (Child-Pugh Class C) is not recommended.
Renal Insufficiency
The pharmacokinetics of valdecoxib have been studied in
patients with varying degrees of renal impairment. Because
renal elimination of valdecoxib is not important to its
disposition, no clinically significant changes in valdecoxib
clearance were found even in patients with severe renal
impairment or in patients undergoing renal dialysis. In
patients undergoing hemodialysis the plasma clearance (CL/F)
of valdecoxib was similar to the CL/F found in healthy elderly
subjects (CL/F about 6 to 7 L/hr.) with normal renal function
(based on creatinine clearance).
NSAIDs have been associated with worsening renal function
and use in advanced renal disease is not recommended (see
PRECAUTIONS—Renal Effects).
Drug Interactions
Also see PRECAUTIONS Drug
Interactions.
General
Valdecoxib undergoes both P450 (CYP) dependent and non-P450
dependent (glucuronidation) metabolism. In vitrostudies
indicate that valdecoxib is not a significant inhibitor
of CYP 1A2,3A4,or 2D6 and is only a weak inhibitor of CYP
2C9 and 2C19 at therapeutic con-centrations. The P450-mediated
metabolic pathway of valdecoxib predominantly involves the
3A4 and 2C9 isozymes. Using prototype inhibitors and substrates
of these isozymes,the following results were obtained. Coadministration
of a known inhibitor of CYP 2C9/3A4 (flu-conazole) and a
CYP 3A4 (ketoconazole) inhibitor enhanced the total plasma
exposure (AUC) of valdecoxib.Coadministration of valdecoxib
with warfarin caused a small,but statistically significant
increase in plasma exposures of R-warfarin and S-warfarin,and
also in the pharmacodynamic effects (International Normalized
Ratio–INR) of warfarin.(See PRECAUTIONS—Drug Interactions.)
Coadministration of valdecoxib,or its injectable prodrug,with
substrates of CYP 2C9 (propofol) and CYP 3A4 (midazolam,alfentanil,
fentanyl) did not inhibit the metabolism of either substrate.
Coadministration of valdecoxib with a CYP 3A4 substrate
(gly-buride) or a CYP 2D6 substrate (dextromethorphan) did
not result in clinically important inhibition in the metabolism
of these agents.
CLINICAL STUDIES
The efficacy and clinical utility of BEXTRA Tablets
have been demonstrated in osteoarthritis (OA),rheumatoid
arthritis (RA) and in the treatment of primary dysmenorrhea.
Osteoarthritis
BEXTRA was evaluated for treatment of the signs
and symptoms of osteoarthritis of the knee or hip,in five
double-blind,randomized, controlled trials in which 3918
patients were treated for 3 to 6 months.BEXTRA was shown
to be superior to placebo in improvement in three domains
of OA symptoms:(1) the WOMAC (Western Ontario and McMaster
Universities) osteoarthritis index,a composite of pain,stiffness
and functional measures in OA,(2) the overall patient assessment
of pain,and (3) the overall patient global assess-ment.The
two 3-month pivotal trials in OA generally showed changes
statistically significantly different from placebo,and comparable
to the naproxen control,in measures of these domains for
the 10 mg/day dose.No additional benefit was seen with a
valde-coxib 20-mg daily dose.
RheumatoidArthritis
BEXTRA demonstrated significant reduction compared
to placebo in the signs and symptoms of RA,as measured by
the ACR (American College of Rheumatology) 20 improvement,a
composite defined as both improvement of 20% in the number
of tender and number of swollen joints,and a 20% improvement
in three of the following five: patient global,physician
global,patient pain,patient function assessment,and C-reactive
protein (CRP).BEXTRA was evaluated for treatment of the
signs and symptoms of rheumatoid arthritis in four double-blind,randomized,controlled
studies in which 3444 patients were treated for 3 to 6 months.The
two 3-month pivotal trials compared valdecoxib to naproxen
and placebo.The results for the ACR20 responses in these
trials are shown below (Table2).Trials of BEXTRA in rheumatoid
arthritis allowed concomitant use of corticosteroids and/or
disease-modifying anti-rheumatic drugs (DMARDs),such as
methotrexate,gold salts,and hydroxychloroquine.No additional
benefit was seen with a valdecoxib 20-mg daily dose.
Table 2 : ACR20 Response Rate (%)
in Rheumatoid Arthritis
| |
Study 1 |
Study 2 |
|
BEXTRA 10 mg/day
|
49%**(103/209)
|
46%**(103/226)
|
|
BEXTRA 20 mg/day
|
48%** (102/212)
|
47%* (103/219)
|
|
Naproxen500 mg BID
|
44%* (100/225)
|
53%**(115/219)
|
|
Placebo
|
32% (70/222)
|
32% (71/220)
|
|
* p<0.01;** p<0.001 compared to placebo
|
Primary Dysmenorrhea
BEXTRA was compared to naproxen sodium 550 mg in two placebo-controlled
studies of women with moderate to severe primary dys-menorrhea.
The onset of analgesia was within 60 minutes for BEXTRA
20 mg. The onset, magnitude, and duration of analgesic effect
with BEXTRA 20 mg were comparable to naproxen sodium 550mg.
Safety Studies
Gastrointestinal (GI) Endoscopy Studies with Therapeutic
Doses:
Scheduled upper GI endoscopic evaluations were performed
with BEXTRA at doses of 10 and 20 mg daily in over 800 OA
patients who were enrolled into two randomized 3-month studies
using active comparators and placebo controls (Study 3 and
Study 4).These studies enrolled patients free of endoscopic
ulcers at baseline and compared rates of endoscopic ulcers,
defined as any gastroduodenal ulcer seen endoscopically
provided it was of "unequivocal depth" and at least 3 mm
in diameter.
In both studies, BEXTRA 10 mg daily was associated with
a statistically significant lower incidence of endoscopic
gastroduodenal ulcers over the study period compared to
the active comparators. Figure 1 summarizes the incidence
of gastroduodenal ulcers in Studies 3 and 4 for the placebo,
valdecoxib,and active control arms.
Safety Study with Supratherapeutic Doses: Scheduled
upper GI endoscopic evaluations were performed in a randomized
6-month study of 1217 patients with OA and RA comparing
valdecoxib 20 mg BID (40 mg daily) and 40 mg BID (80 mg
daily) (4 to 8 times the recommended therapeutic dose) to
naproxen 500 mg BID (Study 5).This study also formally assessed
renal events as a primary outcome with supratherapeutic
doses of BEXTRA. The renal endpoint was defined as any of
the following: new/increase in edema, new/increase in congestive
heart failure, increase in blood pressure (BP;>20 mm Hg
systolic,>10 mm Hg diastolic),new/increase in BP treatment,
new/ increase in diuretic therapy, creatinine increase over
30% (or >1.2mg/dL if baseline <0.9 mg/dL),BUN increase over
200% or >50mg/dL,24-hr urinary protein increase to >500
mg (if baseline 0-150 mg or >750 if baseline 151-300 or
>1000 if baseline 301-500), serum potassium increase to
>6 mEq/L, or serum sodium decrease to <130 mEq/L.
Figure 2 summarizes the incidence rates of gastroduodenal
ulcers and renal events that were seen in Study 5.BEXTRA
40 mg daily and 80 mg daily were associated with a statistically
significant lower incidence of endoscopic gastroduodenal
ulcers over the study period compared to naproxen. The incidence
of renal events was significantly different between the
BEXTRA 80 mg daily group and naproxen. The clinical relevance
of renal events observed with supratherapeutic doses (4
to 8 times the recommended therapeutic dose) of BEXTRA is
not known (see PRECAUTIONS—Renal Effects).
Renal Safety at the Therapeutic Chronic Dose:
The renal effects of valdecoxib compared with placebo and
conventional NSAIDs were also assessed by prospectively
designed pooled analyses of renal events data (see definition
above—Supratherapeutic Doses) from five placebo- and active-controlled
12-week arthritis trials that included 995 OA or RA patients
given valdecoxib 10 mg daily. The incidence of renal events
observed in this analysis with valdecoxib 10 mg daily (3%),ibuprofen
800 mg TID (7%),naproxen 500 mg BID (2%) and diclofenac
75 mg BID (4%) were significantly higher than placebo-treated
patients (1%).In all treatment groups, the majority of renal
events were either due to the occurrence of edema or worsening
BP.
Gastrointestinal Ulcers in High-Risk Patients:
Subset analyses were performed of patients with risk factors
(age, concomitant low-dose aspirin use, history of prior
ulcer disease) enrolled in four upper GI endoscopic studies.
Table 3 summarizes the trends seen.
The correlation between findings of endoscopic studies,
and the incidence of clinically significant serious upper
GI events has not been established. Table 3:Incidence of Endoscopic Gastroduodenal Ulcers
in Patients With and Without Selected Risk Factors
|
Risk Factor
|
Placebo-controlled Studies
|
Active-controlled Studies
|
|
Placebo
|
Valdecoxib (10-20 mg daily)
|
Valdecoxib (10-80 mg daily)
|
Ibuprofen 800 mg TID
|
Naproxen 500 mg BID
|
Diclofenac 75 mg BID |
|
|
Age
|
|
<65 yrs
|
3.7%
|
(8/219)
|
3.5%
|
(17/484)
|
3.7%
|
(48/1306)
|
8.2%
|
(9/110)
|
12.8%
|
(51/397)
|
13.2%
|
(34/258)
|
|
³65 yrs
|
5.8%
|
(8/137)
|
4.6%
|
(12/262)
|
7.6%
|
(43/568)
|
21.6%
|
(16/74)
|
22.0%
|
(33/150)
|
18.2%
|
(25/137)
|
|
Concomitant Low Dose Aspirin Use
|
|
no
|
4.4%
|
(13/298)
|
3.2%
|
(21/650)
|
3.8%
|
(64/1671)
|
9.8%
|
(15/153)
|
16.0%
|
(75/468)
|
12.8%
|
(45/351)
|
|
yes
|
5.2%
|
(3/58)
|
8.3%
|
(8/96)
|
13.3%
|
(27/203)
|
32.3%
|
(10/31)
|
11.4%
|
(9/79)
|
1.8%
|
(14/44)
|
|
History of Ulcer Disease
|
|
no
|
4.4%
|
(14/317)
|
3.4%
|
(22/647)
|
4.1%
|
(68/1666)
|
13.8%
|
(22/160)
|
13.3%
|
(63/475)
|
14.7%
|
(52/354)
|
|
yes
|
5.1%
|
(2/39)
|
7.1%
|
(7/99)
|
11.1%
|
(23/208)
|
12.5%
|
(3/24)
|
29.2%
|
(21/72)
|
17.1%
|
(7/41)
|
|
No statistical conclusions can
be drawn from these comparisons. |
Platelets: In four clinical studies with young
and elderly (³65 years) subjects,single and multiple
doses up to 7 days of BEXTRA 10 to 40mg BID had no effect
on platelet aggregation.
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