Title: PharmaNote
ALL VOLUMES CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00087345/00008
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: February 2003
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00008
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Downloads

This item has the following downloads:

February2003 ( PDF )


Full Text















VALDECOXIB:
A NEW COX-2-SPECIFIC
INHIBITOR

Ming Chow, Pharm.D. Candidate


Introduction
Valdecoxib (Bextra) is the newest addition
to the cyclooxygenase-2 (COX-2) inhibitor family
that already includes celecoxib (Celebrex) and ro-
fecoxib (Vioxx). It was approved by the FDA on
November 21, 2001 and is marketed by Pharmacia
and Pfizer, the same makers of celecoxib. Valde-
coxib is an oral agent and is currently indicated for
the relief of the signs and symptoms of osteoarthri-
tis (OA) and adult rheumatoid arthritis (RA) and
for the treatment of primary dysmenorrhea.1 It also
appears to be effective in the treatment of acute
pain, although it is not yet FDA approved for this
indication. In addition, a parenteral form of valde-
coxib, that will be available as the prodrug pare-
coxib, is currently undergoing phase III clinical tri-
als for the management of acute post-surgical
2,3
pain.23
Non-steroidal anti-inflammatory drugs
(NSAIDs) have been widely used to treat arthritis,
menstrual pain, headaches, and other painful condi-
tions due to their ability to relieve the inflammation
process and provide general analgesia. However,
their long-term use is limited by side effects includ-
ing damage to the gastric mucosa and renal toxic-
ity. The most common adverse effect associated
with NSAID use is gastrointestinal (GI) toxicity,
often resulting in ulcers, bleeding, or perforations.
Currently, none of the available NSAIDs is free of


GI complications.
The clinical effects of traditional NSAIDs
are based on inhibiting the COX enzyme, which is
responsible for the conversion of arachidonic acid
to prostaglandin (PG).4 Two COX isoforms have
been identified: COX-1 and COX-2. COX-1 is
constitutively expressed and is present as the main
COX enzyme in the gastric mucosa, where it is the
primary source of PGs. Prostaglandins are in-
volved with cytoprotection of gastric mucosa, he-
mostasis, and renal physiology, as well as being
produced in response to inflammation and pain. In
contrast, COX-2 is inducibly expressed during the
inflammation process. It is believed that inhibition
of COX-2 is the basis for the anti-inflammatory,
antipyretic, and analgesic effects of these agents,
while inhibition of COX-1 is the cause of adverse
GI effects.
The development of the COX-2 selective
inhibitors, while minimally inhibiting COX-1, has
proved to be very effective in providing relief of
pain and inflammation with improved GI tolerabil-
ity. As an example, since its introduction in 1999,
COX-2 inhibitors now account for about 60% of
the antiarthritic drug market.5 Total sales of Cele-
brex and Vioxx in the year 2000 were estimated
to be more than $3 billion, with new and refill pre-
scriptions rising to 121.3 million. This article will
review the pharmacology, pharmacokinetics, clini-
cal trials, adverse effects, contraindications, drug
interactions, dosing, and cost of therapy with valde-
coxib.

Pharmacology/Pharmacokinetics
The COX enzyme plays a key role in the
biosynthesis pathway of PGs. The inhibition of
COX-2 by valdecoxib is believed to result from a
three-step kinetic mechanism.6 The first two steps


m
Pha rma Note Volume 18, Issue 5 February 2003


SPharmaNote


VOLUME 18, ISSUE 5 FEBRUARY 2003
tlL


PharmaNote


Volume 18, Issue 5 February 2003







Table 1: Pharmacokinetic parameters of ValdecoxibI


Cimax
Tmax
Oral bioavailability
AUC
Effect of food
Effect of antacid
(Al/Mg OH)
Plasma protein binding
Volume of distribution

Metabolism

Excretion
Oral clearance


161 mg/L
-3 hours
83%
1479 mg-hr/L
Tmax delayed 1-2 hrs, but no sig-
nificant effect on AUC or Cmax.
No effect on AUC.
98%
86 L
Mainly CYP450 3A4 and 2C9.
Also, non-P450 dependent path-
ways (i.e. glucuronidation).
70% excreted in urine as me-
tabolites, 20% as glucuronide.
6 L/hr
8-11 hours


Cmx Maximum plasma concentration; Tm,= Time to Cm ; AUC = Area
under curve; T1/2= Half-life

are reversible equilibrium processes, leading to an
irreversible reaction between enzyme and inhibitor.
It is this third step that is postulated to contribute to
the selectivity for COX-2. The first step may in-
volve an interaction between the inhibitor and a hy-
drophobic pocket on the COX enzyme surface lead-
ing to the active COX site. The second step is hy-
pothesized to involve some conformational changes
so that the inhibitor moves to the active site. The
final step involves the inhibitor binding to the en-
zyme to form an irreversible complex. Binding of
valdecoxib to the COX-2 enzyme now prevents for-
mation of PGs, leading to a decrease in pain and in-
flammation.
Some of the pharmacokinetic characteristics
of valdecoxib are presented in Table 1. These val-
ues are based on steady state plasma concentrations
in healthy male subjects (n=8, ages 20-42 years).1

Clinical Trials
Approval of valdecoxib by the FDA was
given based on the results of 5 randomized, pla-
cebo-controlled trials in 3,918 patients with OA of
the knee or hip treated for 3 to 6 months; on 4 ran-
domized, placebo-controlled trials in 3,444 patients
with RA treated for 3 to 6 months; and on 2 pla-
cebo-controlled studies of women (number unspeci-
fied) with moderate to severe primary dysmenor-
rhea.1'7 These studies demonstrated that valde-


Table 3. ACR 20 Response Rate (%) in RA1
Drug/Dose Study 1 Study 2
Valdecoxib 10 mg/day 49% (103/209) 46% (103/226)
Valdecoxib 20 mg/day 48% (102/212) 47% (103/219)


Naproxen 500 mg bid
Placebo


44% (100/225)
32% (70/222)


53% (115/219)
32% (71/220)


coxib was significantly superior over placebo and
exhibited comparable efficacy to the NSAID
naproxen for all three indications. The results of
these trials have not been published to date, but
several of them have been presented as abstracts at
clinical meetings. The available studies are dis-
cussed below and summarized in table 2.

Osteoarthritis
The 3 randomized, placebo-controlled, dou-
ble-blinded, multi-center trials assessed the efficacy
of valdecoxib for the treatment of the signs and
symptoms of osteoarthritis of the knee or hip. All
of these studies looked at improvement in three ar-
eas of OA symptoms: overall patient assessment of
pain using the visual analog scale, the patient's
global assessment, and the WOMAC (Western On-
tario and McMaster Universities) OA index, a com-
posite of pain, stiffness, and functional measures in
osteoarthritis. Fiechtner et al. studied valdecoxib in
doses of up to 10 mg bid compared to naproxen 500
mg bid and placebo in 642 patients with OA of the
knee.8 This six-week study found valdecoxib (5
mg, 10 mg qd, and 10 mg bid) to be comparable in
efficacy to naproxen and demonstrated a dose-
dependent improvement, with no additional benefit
conferred with doses above 5 mg bid or 10 qd.
Kivitz et al. evaluated 1,019 patients with os-
teoarthritis of the knee for 12 weeks and found
greater improvement of arthritic symptoms with
valdecoxib in doses of up to 20 mg when compared
with naproxen 500 mg bid.9 Also, this study inves-
tigated the incidence of gastroduodenal ulcers by
pre- and post-therapy endoscopies. However, the
criteria for ulcer definition were not specified. The
higher incidence of ulcers seen in the naproxen
group were statistically significant only at valde-
coxib doses of 5 and/or 10 mg. Makarowski et al.
studied 466 patients with osteoarthritis of the hip
for 12 weeks and found a greater improvement in
the overall assessment of arthritic relief with valde-


Pha rma Note Volume 18, Issue 5 February 2003


PharmaNote


Volume 18, Issue 5 February 2003







Table 2. Summary of Valdecoxib Clinical Studies7

Authors Study Design Treatment Groups Clinical Findings
Patients
r e a OA Val 0.5, 1.25, 2.5, 5, All Val doses except 0.5 mg showed greater improvement over
Fiechtner et al.
20018 R, DB, PC, PG, MC 10 mg bid, 10 mg qd; placebo. Val 5 mg bid, 10 mg qd, and 10 mg bid have similar
N = 642 Nap 500 mg bid; P efficacy to Nap.
Kiviz et OA 1 o Comparable improvement with Val 10 mg and 20 mg and Nap.
Kwitz et al. Val 5, 10, or 20 mg qd;
20019 R, DB, PC, MC Nap 500 mg bid Higher ulcer incidence with Nap (10%) vs. Val 5 mg (3%), Val
N =1,019 10 mg (3%), and Val 20 mg (5%).
OA
Makarowski et al. D Val 5 or 10 mg qd; Greater improvement with Val 5 and 10 mg over placebo.
200110 R, DB, PC, MC Nap 500 mg bid; P Similar efficacy with Val 10 mg and Nap.
RA 466
Bensen et al. RA Val 10, 20, or 40 mg; Greater ACR-20 rates with all Val doses (46-52%) and Nap
200111 R, DB, PC; Nap 500 mg bid; P (44%-51%) than with placebo (30-36%).
N 1,089
Se PD Single doses of Val Greater pain intensity relief with Val 40 mg at all time points.
Torri et al.
200112 R, DB, PC 20 mg and 40 mg; Greater pain reduction on time-weighted scales with both Val
N = 120 Nap 550 mg; P doses and Nap over placebo.
AP
Camu et al. 34.5% and 38.9% reduction of mean morphine consumption
200213 R, DB, PC, MC Val 20 or 40 mg bid; P
2002N 217 with Val 20 and 40 mg, respectively, 0-24 hours postop.
AP Longer median time to rescue med postop with all Val doses
Daniels et al. Val 10, 20 40, or (9:04 to >24:00) vs. placebo (2:59). Less % of pts requiring
200114 P 80 mg; P rescue med postop with all Val doses (32-67%) vs. placebo
N 466 (95%).
Se AP Quicker onset of analgesia, improved pain relief, and lower
Fricke et al.
200215 R, DB, PC Val 40 mg; Rof 50 mg pain intensity with Val vs. Rof after single dose; Superior effi-
N = 203 cacy with Val in % of pts requiring rescue med.
OA = Osteoarthritis; RA= Rheumatoid arthritis; PD -Primary dysmenorrhea; AP = Acute Pain; R = Randomized; DB = Double-blind; PC = Placebo-controlled;
PG = Parallel-group; MC = Multicenter; Val = Valdecoxib; Nap = Naproxen; P = Placebo


coxib 5 and 10 mg compared to placebo. In addi-
tion, the authors found the 10 mg dose to be equally
efficacious as naproxen 500 mg bid. 10

Rheumatoid arthritis
Two important three month trials compared
valdecoxib to naproxen and placebo in the reduc-
tion of the signs and symptoms of RA, as measured
by the ACR (American College of Rheumatology)
20 index. This index is a composite defined as a
20% improvement in the number of tender and
swollen joints, as well as, a 20% improvement in
three of five other measures (patient global, physi-
cian global, patient pain, patient function assess-
ment, and the erythrocyte sedimentation rate).1
These results are briefly shown in table 3.
Only one study, discusses the clinical effi-
cacy of valdecoxib in the treatment of the signs and
symptoms of rheumatoid arthritis. Bensen et al.
evaluated valdecoxib in doses up to 40 mg qd in
1,089 patients compared to naproxen and placebo.11
A significant improvement in response was seen
with greater ACR 20 rates in all three valdecoxib


mhcrmln aot


doses compared to placebo, but there was no
change compared to the naproxen groups. Interest-
ingly, the 20 mg dose demonstrated to be as effica-
cious as the 40 mg dose and appeared to be better
tolerated.

Primary dysmenorrhea
Torri et al. compared two different doses of
valdecoxib to naproxen and placebo over four
months in 120 women with moderate to severe pri-
mary dysmenorrhea.12 All active treatments re-
sulted in significant pain relief and reduction in
pain intensity over 8 and 12 hours. Valdecoxib was
comparable to naproxen, with valdecoxib 40 mg
being significantly better than 20 mg on the 12-
hour pain intensity measurement. Also, valdecoxib
40 mg provided 5 more hours of pain relief than the
20 mg dose.

Acute pain
Valdecoxib has been studied in the setting
of postoperative analgesia, although it does not
have FDA approval for this indication to date. The


Volume 18, Issue 5 February 2003


1


I I I I I I IP I W







Table 4. Adverse events (%) with >2% incidence in OA or RA patients treated with valdecoxib for >3 months1

Placebo Valdecoxib 10 mg Valdecoxib 20 mg
Adverse event
(n = 973) (n = 1214) (n = 1358)
Hypertension 0.6 1.6 2.1
Back pain 1.6 1.6 2.7
Peripheral edema 0.7 2.4 3.0
Flu-like symptoms 2.2 2.0 2.2
Accidental injury 2.8 4.0 3.7
Dizziness 2.1 2.6 2.7
Headache 7.1 4.8 8.5
Abdominal fullness 2.0 2.1 1.9
Abdominal pain 6.3 7.0 8.2
Diarrhea 4.2 5.4 6.0
Dyspepsia 6.3 7.9 8.7
Flatulence 4.1 2.9 3.5
Nausea 5.9 7.0 6.3
Myalgia 1.6 2.0 1.9
Sinusitis 2.2 2.6 1.8
Upper respiratory tract infection 6.0 6.7 5.7
Rash 1.0 1.4 2.1


study by Camu et al. in 2002 was a multicenter,
double-blind, parallel-group involving 217 patients
and investigated the opioid-sparing effects, analge-
sic efficacy, and safety of valdecoxib.13 Patients
undergoing hip arthroplasty were given active drug
or placebo 1 to 3 hours preoperatively and were fol-
lowed postoperatively for 48 hours. Patients who
received valdecoxib 20 mg or 40 mg bid required
significantly less morphine than placebo. Admini-
stration of valdecoxib before and after surgery re-
duced the amount of morphine needed for pain re-
lief and provided greater analgesic efficacy when
compared to morphine alone. There was no signifi-
cant difference between the percentages of patients
requiring morphine at scheduled time points above
48 hours in the valdecoxib versus the placebo
groups.
Two recent studies evaluated the efficacy of
valdecoxib in relieving postoperative pain associ-
ated with oral surgery. One study presented in ab-
stract form by Daniels et al. was a randomized,
double-blinded, placebo-controlled single-dose
study of 466 patients with valdecoxib.14 The re-
sults suggest that valdecoxib is effective in increas-
ing the median time to rescue medication, as well
as, in decreasing the number of patients requiring
rescue medication after surgery compared to pla-
cebo. Finally, a recent randomized, double-blinded
study published by Fricke et al. evaluated the anal-


gesic efficacy of valdecoxib 40 mg compared to ro-
fecoxib 50 mg and placebo.15 Results showed that
valdecoxib was superior to placebo in all areas of
improvement, including onset of analgesia, pain re-
lief, pain intensity, and patient satisfaction.

Adverse Effects
Table 4 summarizes the adverse events oc-
curring in >2% of patients treated with valdecoxib
10 mg or 20 mg/day. This data comes from 7 con-
trolled clinical trials with a duration of 3 or more
months.' Of these patients, 2665 had OA and 2684
had RA. In addition, over 4000 of them received a
chronic total daily dose =10 mg/day and about
2800 received this dose for at least 6 months, while
988 received it for over a year.

Contraindications and Warnings
Valdecoxib is contraindicated in patients
with known hypersensitivity to any of the COX-2
inhibitors.' Valdecoxib should not be given to pa-
tients with asthma, urticaria, or allergic-type reac-
tions to aspirin or non-steroidal anti-inflammatory
drugs due to the risk of anaphylaxis.16 This in-
cludes patients with the aspirin triad (asthma with
rhinitis with or without nasal polyps or broncho-
spasm). Also, valdecoxib should be used with cau-
tion in patients on concurrent corticosteroid ther-
apy. Patients with a history of GI bleeding or ulcers


-
Pha rma Note Volume 18, Issue 5 February 2003


PharmaNote


Volume 18, Issue 5 February 2003









Aspirin

Warfarin

Methotrexate
ACE-Inhibitors

Furosemide

Dextromethorphan

Lithium
Fluconazole and
ketoconazole
Glyburide


should be aware that serious GI toxicity such as
bleeding, ulceration, or perforation of the stomach,
small intestine, or large intestine can occur at any
time when treated with NSAIDs. 1 Patients with
advanced renal or hepatic disease are not advised
to take valdecoxib because of a lack of safety
data. 116
Patients with fluid retention, hypertension,
or heart failure are advised to use valdecoxib with
caution. 16,17 It should not be administered to pa-
tients with preexisting asthma since there is a pos-
sibility that aspirin-sensitive asthma can cross-react
with NSAIDs to cause severe bronchospasms. 1 Pa-
tients with mild or moderate hepatic impairment
are cautioned about the use of valdecoxib since ele-
vations of aminotransferases (AST and AST) may
occur; therefore, they should be monitored for
signs and symptoms of liver dysfunction.1 Long-
term use of NSAIDs has been associated with renal
injury so patients with mild or moderate renal im-
pairment should be monitored carefully when
treated with valdecoxib. 1 In particular, caution
should be taken in patients with serious dehydra-
tion; it is advisable to rehydrate before beginning
treatment. 1,16 Also, valdecoxib is classified as a
pregnancy Category C drug and should be avoided
in late pregnancy due to the risk of premature clo-
sure of the ductus arteriosus and other teratogenic
effects.17 In the pediatric population (<18 yo),
safety and effectiveness of valdecoxib has not been
studied so precaution is advised. 1,16,17


Table 5. Drug-Drug Interactions with Valdecoxib1'7'16'17


PharmaNot Vlum 18 Isue5 Fbrury 00


Does not affect cardioprotective effect
but increases risk of GI complications.
Increase in plasma exposure of warfarin
and risk of increased anticoagulation.
No effect on plasma exposure or renal
clearance of methotrexate.
May decrease antihypertensive effects.
Decreased response to furosemide due
to inhibition of renal prostaglandin syn-
thesis.
Increased levels of dextromethorphan
due to CYP 2D6 and 3A4 inhibition.
Decreased clearance and increased
serum levels of lithium (monitor).
Increased blood levels of valdecoxib due
to 3A4 and 2C9 inhibition
No effect.


Drug Interactions
In general, metabolism of valdecoxib occurs
via CYP 3A4 and 2C9 with glucuronidation being a
minor (20%) route of metabolism. 1,7 In vitro stud-
ies show valdecoxib to be a moderate inhibitor of
CYP 2C19 and a weak inhibitor of both 3A4 and
2C9.1 Studies investigating potential drug interac-
tions were done with valdecoxib and its prodrug,
parecoxib. 1 Some of the known drug interactions
of valdecoxib are reported in Table 5.

Dosing and Administration
The recommended oral dose of valdecoxib
is the same for OA and RA: 10 mg once a day. The
recommended dose for primary dysmenorrhea is 20
mg twice daily. A dose of 20 mg twice a day has
also been used in the treatment of acute pain; how-
ever, this indication is not FDA-approved. As men-
tioned earlier, valdecoxib will soon be available in
an IV or IM form for use with postoperative pain.
Recent clinical trials have used doses ranging from
20 to 80 mg, with the 20 mg and 40 mg often
showing analgesic efficacy.3
In certain special populations, doses of val-
decoxib may need to be adjusted. For mild to mod-
erate hepatic impairment, doses of valdecoxib
should not exceed 10 mg, and signs of edema
should be monitored. However, no dosage adjust-
ment is needed for mild to moderate renal impair-
ment. In the geriatric population, no special dosage
adjustment is needed unless they have poor general
health or other precautions that may warrant a de-
crease in dose. As discussed earlier, caution is ad-
vised for use in children under 18 years of age be-
cause safety and efficacy has not been evaluated in
this population yet.

Cost
The average cost of a 30-day supply of Bex-
tra from three local community pharmacies is
$84.01, ranging from $80.33 to $87.99. The price
is the same for the 10 mg or 20 mg tablets.

Summary
Valdecoxib is the newest FDA-approved
COX-2 inhibitor for the treatment of OA, RA, and
primary dysmenorrhea. Future indications include
its use in the postoperative analgesic setting, par-
ticularly with the availability of the parenteral dos-


PharmaNote


Volume 18, Issue 5 February 2003







age form. Valdecoxib appears to be similar in pro-
file to the other COX-2 inhibitors and comparable
in efficacy to other NSAIDs like naproxen.

References
1. Bextra Prescribing Information, Pharmacia/
Pfizer, February 2002.
2. Jain, KK. Evaluation of intravenous parecoxib
for the relief of acute post-surgical pain. Expert
Opin Investig Drugs 2000; 9(11): 2717-2723.
3. Cheer SM and Goa KL. Parecoxib (Parecoxib
sodium). Drugs 2001; 61(8): 1133-1141.
4. www.medscape.com/viewprogram/1000-pnt.
NSAIDs, coxibs, and cardio-renal physiology: a
mechanism-based evaluation. 2002.
5. www.imshealth.com. News articles on: Antir-
heumatic non-steroidals and COX-2 inhibitors
impact marketplace. 2001.
6. Walker MC et al. A three-step kinetic mecha-
nism for selective inhibition of cyclooxygenase-
2 by diarylheterocyclic inhibitors. Biochem J
2001; 357: 709-718.
7. Goldman M and Schutzer S. Valdecoxib. For-
mulary 2002; 37:68-77.
8. Fiechtner JJ, et al. A double-blind, placebo-
controlled dose ranging study to evaluate the
efficacy of valdecoxib, a novel COX-2 specific
inhibitor, in treating the signs and symptoms of
osteoarthritis of the knee. Presented
9. .at: European Congress of Rheumatology; June
2001; Prague, Czech Republic. Abstract.
10. Kivitz A, et al. The COX-2 specific inhibitor
valdecoxib is as effective as the conventional
NSAID naproxen in treating symptomatic os-
teoarthritis of the knee and demonstrates re-
duced gastrointestinal ulceration. Presented at:
American College of Rheumatology 65th An-
nual Scientific Meeting; November 2001; San
Francisco, CA. Abstract.
11. Makarowski W, et al. The COX-2 specific in-
hibitor is effective in treating symptomatic os-
teoarthritis of the hip. Presented at: American
College of Rheumatology 65th Annual Scien-
tific Meeting; November 2001; San Francisco,
CA. Abstract.
12. Bensen W, et al. Valdecoxib, a new COX-2
specific inhibitor, is effective in treating the
signs and symptoms of rheumatoid arthritis.
Presented at: American College of Rheumatol-


ogy 65th Annual Scientific Meeting; November
2001; San Francisco, CA. Abstract.
13. Torri S, et al. The cyclooxygenase (COX) -2
specific inhibitor valdecoxib effectively treats
14. primary dysmenorrhea. Presented at: 57th An-
nual Meeting of the American Society of Re-
productive Medicine; October 2001; Orlando,
FL. Abstract.
15. Camu F, et al. Valdecoxib, a COX-2 specific
inhibitor, is an efficacious, opioid-sparing anal-
gesic in patients undergoing hip arthroplasty.
Am J Ther 2002; 9:43-51.
16. Daniels SE, et al. Preoperative valdecoxib, a
COX-2 specific inhibitor, provides effective
and long lasting pain relief following oral sur-
gery. Presented at: American Society of Anes-
thesiologists Annual Meeting; October 2001;
New Orleans, LA. Abstract.
17. Fricke J, et al. Valdecoxib is more efficacious
than rofecoxib in relieving pain associated with
oral surgery. A J Ther 2002; 9: 89-97.
18. www.drugguide.com/documents/monographs/
html/valdecoxib.htm. 2002.
19. www.edruginfo.com/dud valdecoxib.htm.
2002.




Strattera (atomoxetine) is a selective
norepinephrine reuptake inhibitor used in the
treatment of attention-deficit/hyperactivity
disorder (ADHD). It has a different
mechanism of action from the stimulant-like
drugs that have been used to treat ADHD in
the past. It is thought to selectively inhibit
the pre-synaptic norepinephrine transporter
and does not appear to have a potential for
abuse so it is not classified as a controlled
substance. The initial dose for children
=6yrs/=70kg is 0.5 mg/kg/day given qam or
in 2 divided doses. The dose may be
increased after 3 days to a target of 1.2 mg/
kg/day. The initial dose for adults and
children =6yrs/=70kg is 40 mg/day given
qam or in 2 divided doses. The dose may be
increased every 3 days to a target of 80 mg/
day. Adjustment is necessary in patients with
hepatic impairment and those on CYP 2D6


Pha rma Note Volume 18, Issue 5 February 2003


PharmaNote


Volume 18, Issue 5 February 2003







LEXAPROTM
A NEW SELECTIVE SEROTONIN
REUPTAKE INHIBITOR

Surjit Singh, Pharm.D. Candidate



Introduction
Depression is a major public health problem
in the United States. The National Comorbidity
Survey reports that 17% of the United States popu-
lation has had or will have a major depressive dis-
order in their lifetime and more than 10% has had
an episode of depression within the last year.1 De-
pression is more prevalent in females than males
and adults 25 to 44 years of age experience the
highest rates of depression.1 Also, even though de-
pression may occur regardless of age or gender,
rates of alcoholism, substance abuse, suicide at-
tempts, and deaths are higher in these young pa-
tients. In addition, patients with depression are
more likely to develop co-morbid psychiatric disor-
ders. Currently, there are six Selective Serotonin
Reuptake Inhibitors (SSRIs) that are approved for
the treatment of depression. LexaproTM
(escitalopram), is the latest in this class. It was ap-
proved in August 2002 by the Food and Drug Ad-
ministration (FDA) and is being marketed by For-
est Pharmaceuticals, Inc.
Escitalopram is the S-enantiomer of citalo-
pram. Animal studies demonstrate that the biologi-
cal effects of citalopram reside within the S-
enantiomer.2 However, clinical trials have been un-
able to demonstrate escitalopram's superiority over
citalopram and there is no evidence that escitalo-
pram has a lower frequency of side effects than the
parent compound. Nevertheless, it may have the
potential advantage of a quicker onset of action.3

Pharmacodynamics
Escitalopram enhances the effects of sero-
tonergic activity in the central nervous system
(CNS) by inhibiting the neuronal reuptake of sero-
tonin. Like other SSRIs, escitalopram is highly se-
lective for serotonin and has minimal effects on
other neurotransmitters. Therefore, it causes less
sedation, anticholinergic and cardiovascular effects
than the tricyclic antidepressants.


Pharmacokinetics
Pharmacokinetic parameters of escitalopram
are similar to citalopram. A 20 mg dose of escita-
lopram is bioequivalent to 40 mg of citalopram.
Escitalopram is extensively metabolized by
CYP450 isozymes 2C19, 2D6, and 3A4. Therefore,
theoretically, impaired activity of any one of these
isozymes should have a minimal effect on the net
metabolic clearance.4 Escitalopram is metabolized
to two inactive metabolites: S-demethylcitalopram
(S-DCT) and S-didemethylcitalopram (S-DDCT).
Escitalopram is recovered in the urine as citalopram
(8%) and S-DCT (10%). Absorption of escitalo-
pram is not affected by food; whereas, it's area un-
der the curve (AUC) and half-life are increased by
approximately 50% in elderly patients. The elimi-
nation half-life of escitalopram is approximately 25
hours which makes it ideal for once daily dosing.

Indication and Dosing
Escitalopram is approved for the treatment
of major depressive disorder; however, initial stud-
ies have shown that within 1-2 weeks escitalopram
also demonstrates significant antianxiety and anti-
depressant effects. The initial adult dose is 10 mg
by mouth once daily which can be increased to 20
mg once daily after one week. Adverse effects ap-
pear to be dose related and there is no available
dosing data for adolescents and children. Escitalo-
pram is extensively metabolized in the liver and
thus therapy must be initiated and maintained at the
lower end of the dosage range (i.e. 10 mg once
daily) in patients with hepatic impairment. Specific
guidelines for renal dosage adjustments are not
available.

Clinical Efficacy Trials
The efficacy of escitalopram in the treat-
ment of major depressive disorder has been based
in part from the established effectiveness of race-
mic citalopram. In addition, two 8-week double-
blinded, placebo-controlled, randomized studies
were done to show it's effectiveness in the treat-
ment of depression.
In the first study, 380 patients were random-
ized to escitalopram 10 mg/day or placebo. At the
end of the 8 weeks, the escitalopram group showed
a statistically significant improvement on the Mont-
gomery Asberg Depression Rating Scale (MADRS)
compared to placebo. In addition, in further by-


Ph ra ot Vlue 8,Isue5 ebuay 00


PharmaNote


Volume 18, Issue 5 February 2003








Table 1. Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled Clinical Trials6


Body System / Adverse Event


Autonomic Nervous System Disorders
Dry Mouth
Sweating Increased
Central & Peripheral Nervous System Disorders
Dizziness
Gastrointestinal Disorders
Nausea
Diarrhea
Constipation
Indigestion
Abdominal Pain
General
Influenza-like Symptoms
Fatigue
Psychiatric Disorders
Insomnia
Somnolence
Appetite Decreased
Libido Decreased
Respiratory System Disorders
Rhinitis
Sinusitis
Urogenital
Ejaculation Disorder
Impotence
Anorgasmia


Percentage of Patients Reporting Event
Escitalopram Placebo
(N=715) (N=592)


15%
8%
3%
3%
2%


<1%
<1%
<1%


week efficacy analyses, the effect of escitalopram
was consistently larger than that for placebo begin-
ning at week 1 as measured by the Clinical Global
Impression Improvement Score.5
The second study was a fixed dose study of
escitalopram 10 and 20 mg/day compared to pla-
cebo and citalopram 40 mg/day. This study was
done in outpatients between the ages of 18 and 65
who met the DSM-IV criteria for major depressive
disorder. The authors concluded that the escitalo-
pram 10 and 20 mg/day treatment groups showed
significantly greater and similar improvements
compared to placebo on the MADRS. Furthermore,
there was no significant difference in the incidence
of adverse events between placebo and escitalo-
pram 10 mg (79.0% vs. 70.5% respectively;
p=0.14) or between citalopram 40 mg and escitalo-
pram 20 mg (86.4% vs. 85.6% respectively;
p<0.01).6


The long-term efficacy of escitalopram in
major depressive disorder has not been evaluated.
However, the longer term efficacy of racemic cita-
lopram is well established. In two longer term stud-
ies, patients who responded to an initial 6 to 8
weeks of citalopram therapy were randomized to
either continue racemic citalopram or to take pla-
cebo for up to 6 months. In both studies, patients
who continued receiving racemic citalopram ex-
perienced significantly lower relapse rates.
In a third longer-term trial, patients who
were diagnosed with recurrent major depressive
disorder and in the past had responded to racemic
citalopram were randomized to either continue their
citalopram dose or to switch to placebo. Patients
that continued receiving the racemic citalopram
treatment experienced significantly lower relapse
rates over the subsequent 72 weeks compared to
those receiving placebo.


Pha rma NoteVolume 18, Issue 5 February 2003


PharmaNote


Volume 18, Issue 5 February 2003







Table 2. Incidence of Common Adverse Events in Patients Receiving Placebo, 10 mg/day Escitalopram, or 20 mg/day
Escitalopram6
Adverse Placebo 10 mg/day Escitalopram 20 mg/day Escitalopram
Event (N=311) (N=310) (N=125)
Insomnia 4% 7% 14%
Diarrhea 5% 6% 14%
Dry Mouth 3% 4% 9%
Somnolence 1% 4% 9%
Dizziness 2% 4% 7%
Sweating Increased <1% 3% 8%
Constipation 1% 3% 6%
Fatigue 2% 2% 6%
Indigestion 1% 2% 6%


Drug Interactions
In vitro studies indicate that CYP 3A4 and
2C19 are the main enzymes involved in the me-
tabolism of escitalopram. Because escitalopram is
metabolized by multiple enzyme systems, inhibi-
tion of a single enzyme should not significantly de-
crease escitalopram's clearance. However, in one
study, subjects who received racemic citalopram 40
mg/day for 21 days concurrently with cimetidine
400 mg/day for 8 days experienced a 43% increase
in citalopram's AUC. In addition, in vivo data
showed that co-administration of escitalopram and
a single dose of desipramine 50 mg (a substrate for
CYP2D6) resulted in a 100% increase in the AUC
of desipramine. Furthermore, co-administration of
escitalopram 20 mg/day for 21 days resulted in an
82% increase in the AUC of metoprolol.

Adverse Effects
Adverse event information for escitalopram
was collected in a double blind, placebo controlled
trial. Seven hundred fifteen patients with major de-
pressive disorder were exposed to escitalopram and
592 patients were exposed to placebo. The adverse
events were obtained mainly by general inquiry.


Table 3. Cost Comparison Escitalopram

Pharmacy 10 mg/day 20 mg/day

Retail (chain) 69.19 73.09
Internet 64.04 66.83
Independent 71.71 74.49
Mean Price 68.31 71.47


Similar types of events were grouped into a smaller
number of standardized event categories. This in-
formation is summarized in Table 1.
Six percent of the patients in the escitalo-
pram group and 2% in the placebo group discontin-
ued therapy due to adverse events. As seen in Table
2, adverse events were dose dependent with the in-
cidence for the 20 mg/day group being twice that of
the 10 mg/day group.

Cost
The cost for a 30-day supply of escitalo-
pram 10 mg and 20 mg tablets is summarized in
Table 3.

Summary
Escitalopram is the active enantiomer of its
parent compound citalopram. Its efficacy in the
management of major depressive disorder was es-
tablished in two 8-week double-blinded placebo-
controlled randomized studies. Escitalopram ap-
pears to have a quicker onset of action compared to
citalopram and it is effective in the treatment and
maintenance of major depressive disorders with or
without anxiety symptoms; however, superiority to
citalopram has not been demonstrated.8Future com-
parative studies will help to establish its role in the
treatment of major depressive disorder.

References
1. Kando JC et al Depressive Disorders. In: De-
piro JT, editor. Pharmacotherapy: A Patho-
physiologic Approach. 4th ed. Stamford(CT):
Appleton&Lange; 1999 p. 1141-59
2. LexaproT New Drug Monograph. Clinical
Pharmacology Online 2002 August. Gold Stan-


Pha ma Nte Vlume18, ssue5 FeruarL200


PharmaNote


Volume 18, Issue 5 February 2003







dard Media. Available from: URL: http://cpip.
gsm.com
3. Montgomery SA, Loft H, Sachez C, Reines
EH Escitalopram: Clinical Efficacy and onset
of action predicted from a rat model. Pharmacol
Toxicol 2000; 88:282-6
4. Von Moltke L, Greenblatt DJ, Giancarlo GM
Granda BW, Harmatz JS, Shader RI. Escitalo-
pram and its metabolites in vitro: cytochromes
mediating biotransformation, inhibitory effects
and comparison to R-citalopram.Drug Metab
Dispos 2001;29(8): 1102-9.
5. Wade A, Lemming OM, Hedegaard KB. Escita-
lopram 10 mg/day is effective and well toler-
ated in a placebo-controlled study in depression
in primary care. Int Clin Psychopharmacol
2002;17(3):95-102.
6. LexaproTM Product Information. Forest Phar-
maceuticals, Inc. August 2002
7. Kulin NA, Pastuszak A, Sage SR, et al. Preg-
nancy outcome following maternal use of the
new selective serotonin reuptake inhibitors. JA-
MA1998; 279: 609-10
8. Burke WJ, Gergel I, Bose A. Fixed dose trial of
the single isomer SSRI escitalopram in de-
pressed patients. J Clin Psychiatry Apr. 2002
Vol 63(4) p.331-6






TM
Forteo (teriparatide [rDNA origin]) is the
first in a new class of drugs called bone
formation agents that work primarily to
stimulate new bone by preferential stimula-
tion of osteoblastic activity over osteoclastic
activity. This form of recombinant human
parathyroid hormone is indicated for the
treatment of postmenopausal women with
osteoporosis who are at high risk for fracture
and to increase bone mass in men with
primary or hypogonadal osteoporosis who
are at high risk for fracture. The usual dosage
is 20 mcg qd SQ (into thigh or abdominal
wall). Use for more than 2 years is not
recommended.


Abilify' (aripiprazole) is a new agent used in
the treatment of schizophrenia. It is a partial
dopamine agonist with some 5-HT1A
agonistic and 5-HT2A antagonistic activity.
The usual initial adult dose is 10 mg once
daily which can be increased after 2 weeks to
a target of 15 mg once daily. Reduce dose to
one-half of usual if concomitant 3A4 and
2D6 inhibitors. Double dose if concomitant
3A4 inducers.







Avage'TM (tazarotene) cream 0.1% is a retinoic
acid derivative used as an adjunct to a
comprehensive skin care and sunlight
avoidance program, in the mitigation of
facial fine wrinkling, facial mottled hyper-
and hypopigmentation, and benign facial
lentigines. The usual dose for adults is a pea-
sized (14 inch or 5 mm diameter) amount to
face (including eyelids) qhs.






The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.


Klim


PharmaNote


Volume 18, Issue 5 February 2003




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs