Title: PharmaNote
Full Citation
Permanent Link: http://ufdc.ufl.edu/UF00087345/00006
 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: December 2002
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Bibliographic ID: UF00087345
Volume ID: VID00006
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Rights Management: All rights reserved by the source institution and holding location.


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John M. Gregg, Pharm.D. Candidate

Irritable bowel syndrome (IBS) is a chronic
dysfunctional disorder of the gastrointestinal tract
exhibiting varying symptoms, including abdominal
pain, bloating, constipation, diarrhea, and/or altered
bowel function. Approximately 20% of the US
adult population report symptoms consistent with
IBS, and it ranks second only to the common cold
as the most common cause for work absence.1-3 BS
predominantly affects females, with a 2:1 ratio as
compared to males.2 In 1995, the annual costs di-
rectly associated with IBS were estimated to be 8
billion dollars.1
Although the exact pathophysiology is un-
known, postulated mechanisms include: GI tract
dysmotility, psychological disturbances, inflamma-
tory processes, and altered visceral sensitivity.
Also, there is mounting evidence that IBS can oc-
cur after a patient has had infectious gastroenteritis.
It is thought that up to 25% of those admitted for
such diagnosis develop IBS-like symptoms.4 IBS as
a function of a neurological bowel disease has re-
cently come to the forefront of research.
Irritable bowel syndrome can be divided
into 3 main categories: diarrhea predominant, con-
stipation predominant, or mixed constipation-
diarrhea symptoms.4 The criteria for diagnosis, out-
lined in 1999, state that if a patient experiences ab-

dominal pain for 12 or more weeks in a 1 year time
period and has features of two or more of the fol-
lowing: a) Pain relieved upon defecation, b) Onset
associated with a change in frequency of stool, or
c) Onset associated with a change in form
(appearance) of stool, the patient can be diagnosed
with IBS.5
Fortunately, most irritable bowel syndrome
patients require no pharmacotherapy to correct their
symptoms, since diet modification and lifestyle
changes are usually enough to curb effects of IBS.
Current pharmacotherapeutic modalities of therapy
for IBS include fiber intake of 25-30g/day and mild
osmotic laxatives for constipation predominant; an-
ticholinergics, opioids including loperamide for di-
arrhea predominant; and antidepressants or anti-
spasmodics to treat the pain associated with IBS.
Although these treatments are effective in the ma-
jority of patients, there remains a small subgroup of
patients that fail to respond to these therapeutic in-
Lotronex (alosetron hydrochloride) and
Zelnorm(tegaserod maleate) are serotonin recep-
tor modulators that are used in the treatment of re-
sistant IBS symptoms. Serotonin's role in the GI
tract has been well described.4 Roughly 95% of all
of the body's serotonin (5-HT) is located in the gut,
with 10% of that in enteric neurons and the remain-
ing 90% located in the enterochromaffin cells.
Mainly 5-HT3 and 5-HT4 receptor subtypes popu-
late the gut, both of which seem to exert the most
clinically relevant effects of 5-HT. It is these 2 re-
ceptor subtypes that alosetron and tegaserod modu-
late to exert their clinical effect. This article will
discuss the pharmacology, clinical trials, adverse
effects, monitoring parameters, special prescribing
restrictions, dosing and cost associated with each

Pha rma Note Volume 18, Issue 3 December 2002


t l


Volume 18, Issue 3 December 2002

Lotronex" (alosetron)

Alosetron is a selective 5-HT3 receptor an-
tagonist made by GlaxoSmithKline (GSK). The
Food and Drug Administration (FDA) originally
approved it on February 9, 2000.6 After approval,
while in post marketing surveillance, cases of
ischemic colitis that resulted in hospitalizations,
surgery, and deaths were found to occur as a result
of alosetron therapy. Due to these reports, GSK is-
sued a voluntary recall on November 29, 2000.
During the 2 years alosetron was off the market
many women continued to inquire about obtaining
the medication, as alosetron was the only medica-
tion that brought them relief.7 Fortunately, after
new research supported its continued use, GSK
submitted an sNDA, which the FDA approved for
alosetron's reintroduction to the market with re-
strictions on June 7, 2002.7,8 These restrictions are
described in a later section. Alosetron is available
as a 1 mg oral tablet, and is indicated for women
only with severe diarrhea predominant irritable
bowel syndrome that is resistant to other treatment
modalities. Alosetron should not be prescribed to

5-HT3 receptors in the enteric neurons of
the GI tract mediate visceral pain, colonic transit
and GI secretions. Activation of these receptors re-
sults in depolarization of myenteric neurons, which
in turn release acetylcholine and induce fast excita-
tory postsynaptic action potentials. Inhibition of
these receptor sites increases colonic transit time
without increasing orocecal transit time, increases
basal jejunal water and sodium resorption, and in-
creases colonic compliance. This results in a de-
crease of diarrhea associated with irritable bowel

Alosetron is rapidly absorbed after oral ad-
ministration, with absolute bioavailability around
50%. Although absorption is decreased by 25%
when administered with food, it may be given with
or without food. Alosetron is extensively metabo-
lized by the body, primarily by CYP 2C9 (30%),
3A4 (18%), and 1A2 (10%); and roughly 7% is re-
covered unchanged in the urine.6 Alosetron does
not affect the CYP isoenzyme's ability to metabo-

lize other drugs in vivo, and because no one CYP
enzyme is responsible for metabolism, drug interac-
tions involving the CYP system are not clinically
significant.9 Alosetron is rapidly eliminated, with
an estimated half-life of 1.5 hours. Pharmacokinetic
parameters are not clinically affected by hepatic or
renal dysfunction.6 However, in some studies,
alosetron concentrations were elevated 40% in
women over 65 years compared to younger adults.
Alosetron has not been studied in the pediatric

New Restrictions on Prescribing
As part of the agreement to allow alosetron
to be remarketed GlaxoSmithKline had to develop
a risk management program and a prescribing pro-
gram to enroll physicians who wish to prescribe
alosetron.8 To enroll in the prescribing program,
physicians must attest that they are willing and able
to diagnose and treat IBS, diagnose and manage
ischemic colitis, diagnose and manage constipation,
understand the information presented in the pack-
age insert, the Medication Guide, and Patient-
Physician Agreement. The physician must also
educate the patient on the risks and benefits of
alosetron and obtain the patient's signature on the
Patient-Physician Agreement form, sign it, place
the original in the patient's medical record and give
a copy to the patient. The physician must report all
adverse events to Medwatch, and affix the prescrib-
ing program stickers to all prescriptions. All forms
for enrollment and education may be obtained from
GSK or www.lotronex.com or by calling 1-888-
Alosetron may only be prescribed to women
with severe diarrhea-predominant IBS who have
failed to respond to conventional IBS therapy. In
addition, the IBS symptoms must have lasted for a
minimum of 6 months.

Clinical Trials
In a randomized, placebo-controlled trial,
the efficacy and safety of alosetron was tested in
647 female patients with diarrhea predominant IBS.
Male patients were not studied, as earlier clinical
trials demonstrated less efficacy for male patients.
Patients were randomly assigned to either alosetron
1 mg twice daily (n=324) or placebo (n=323) for 12
weeks, followed by a 4-week post-treatment period.
Adequate relief of abdominal pain and discomfort

Pha rma Note Volume 18, Issue 3 December 2002


Volume 18, Issue 3 December 2002

were the primary endpoints, while stool consis-
tency, stool frequency, and urgency were secondary
endpoints. As compared to the placebo group, a
greater percentage of patients on alosetron reported
adequate relief for all 3 months of treatment (41%
vs. 29%). Alosetron also significantly reduced ur-
gency and stool frequency, and increased stool
firmness. Constipation was the most commonly re-
ported side effect in the alosetron group as com-
pared to the placebo group (30% vs. 3%).13 The au-
thors concluded that alosetron was efficacious and
well tolerated in alleviating pain and bowel related
symptoms in this population of women with IBS.
Furthermore, in a subset analysis of the
quality of life scores from the above study popula-
tion, alosetron showed a significant improvement
on all 9 IBSQOL scales compared to placebo
(p<0.05).14 The authors concluded that, in addition
to alleviating bowel related symptoms, alosetron
improved quality of life scores for women with di-
arrhea predominant IBS.
In another randomized, double blind, pla-
cebo controlled trial; alosetron 1mg bid (n=72) was
compared to placebo (n=80) in a 12 week trial in
both men and women. Improvement in adequate
relief was the primary endpoint of this study.
Alosetron significantly increased the proportion of
females, but not males, reporting adequate relief
(p<0.05). Stool frequency, consistency, and per-
centage of days with urgency improved over pla-
cebo (p<0.05).1 It is not known why male patients
do not have an adequate response to alosetron.

Because of new restrictions set forth by the
FDA, patients should be initially prescribed alose-
tron 1mg daily. Upon reevaluation at 4 weeks, if
the patient is still experiencing severe IBS symp-
toms with no evidence of intolerability
(constipation, colitis), the dose may be increased to
1 mg twice daily.

Adverse Events
The FDA has placed a black box warning
on alosetron explaining the risk of ischemic colitis
and serious complications of constipation that have
resulted in hospitalizations, blood transfusions, sur-
gery, and death. Alosetron should be discontinued
in patients who develop constipation or symptoms
of ischemic colitis. In all clinical trials of alosetron,

Table 1. Commonly described adverse events
Adverse Event Placebo Alosetron
Constipation 5% 32%*
Diarrhea 11% 9%
Abdominal Pain 7% 10%
Nausea 5% 6%
Headaches 8% 10%
Urinary Tract infection 4% 5%
Malaise and fatigue 6% 3%
Musculoskeletal pain 8% 7%
Cardiovascular (any event) 4% 6%
Significantly different than placebo (p<0.001)

the most commonly described adverse event was
constipation, and was the most common reason for
early exit of the clinical trial. Table 1 summarizes
the adverse events experienced by patients in clini-
cal trials.6'16 Constipation was the only adverse
event that was significantly higher in the alosetron
group compared to placebo.
Additional reported adverse events include
tachyarrhythmias, breathing disorders, hypnagogic
effects, anxiety, sweating, and urticaria. However,
none of these were significantly different than pla-

Drug Interactions
Although the CYP system is heavily in-
volved in the metabolism of alosetron, in vitro and
in vivo metabolic probe studies have shown that
alosetron does not inhibit CYP enzymes 2C9,
2C19, 3A4, or 2D6 at normal doses. However, In
an in vivo metabolic probe study, alosetron pro-
duced a 30% inhibition of both N-acetyltransferase
and CYP1A2. Although this has not been studied
yet, this could affect concentrations of isoniazid,
procainamide and hydralazine. No effect on the
metabolism of theophylline, alprazolam, or ethinyl
estradiol has been observed.6'9 Also, the effects of
inducers or inhibitors on the CYP system and
alosetron pharmacokinetics has not been studied.
Agents that affect GI motility, such as antidiar-
rheals and laxatives, could alter the efficacy of
alosetron in patients and should be avoided.

Cost of therapy
The retail cost of alosetron for one month of
therapy (30 tablets) ranged from $76.98 to $77.69.

Pha rma Note Volume 18, Issue 3 December 2002


Volume 18, Issue 3 December 2002

Zelnorm (tegaserod)

Tegaserod is a partial 5-HT4 agonist made
by Novartis Pharmaceuticals Corporation. Tegase-
rod was approved by the FDA on July 24, 2002 for
the short-term treatment of women with constipa-
tion predominant IBS. Efficacy has not been estab-
lished in men to date. Tegaserod is an aminogua-
nidine indole derivative of serotonin, and is avail-
able as tegaserod maleate in 2 mg or 6 mg tablets.
Tegaserod, in pre-approval clinical trials, was
shown to be effective in treating abdominal pain,
altered bowel habit (consisting of decreased stool
frequency, hardened stool consistency, straining)
and bloating associated with constipation predomi-
nant IBS in women. 17

Tegaserod is a 5-HT4 partial agonist that has
high affinity for the 5-HT4 receptor subtype, and
moderate affinity for the 5-HT1 receptor. Intestinal
5HT4 receptors are involved in motor, sensory and
secretary functions. It has no appreciable affinity
for the 5-HT3 or the dopamine receptor.18 Tegase-
rod, upon binding and activation of the 5-HT4 re-
ceptor, triggers the release of other neurotransmit-
ters from sensory neurons, primarily calcitonin
gene-related peptide. These actions result in stimu-
lation of the peristaltic reflex and intestinal secre-
tion, and inhibition of visceral sensitivity. In vivo
studies also showed that tegaserod normalized im-
paired motility throughout the gastrointestinal tract.
As a partial agonist, tegaserod has a lower likeli-
hood of inducing receptor desensitization compared
to full agonists, theoretically lowering the likeli-
hood for tachyphylaxis or tolerance.19

The pharmacokinetics of tegaserod are dose
proportional over the 2 to 12 mg dose range.
Tegaserod's absolute oral bioavailability is ap-
proximately 10% when administered to fasting sub-
jects. Administration with food decreases oral ab-
sorption by approximately 50%, therefore it is rec-
ommended for administration before meals. While
gender does not affect the area under the plasma
concentration versus time curve (AUC), the AUC
in elderly female subjects was 40% larger than
young female subjects (p<0.002).20 However, this
effect was not judged to be clinically significant be-

cause this was within the variability of tegaserod's
pharmacokinetic parameters and because of the
shallow dose-response curve of tegaserod.
Tegaserod is roughly 98% protein bound,
primarily to alphal-acid glycoprotein. The esti-
mated terminal half-life is 11 hours. Tegaserod is
metabolized via 2 pathways. The first is presys-
temic acid catalyzed hydrolysis in the stomach,
which is followed by subsequent oxidation and
conjugation producing an inactive metabolite. The
second pathway is direct glucuronidation. Approxi-
mately two-thirds is excreted unchanged in the fe-
ces, and the remainder is excreted as the glucuron-
ide metabolite in the urine.19 Mild and moderate re-
nal and hepatic impairment did not significantly af-
fect the pharmacokinetic parameters of tegaserod.21
Tegaserod has not been studied for use in severe
renal or hepatic impairment, and therefore should
not be used in this population.

Clinical Trials
Three phase III clinical trials were con-
ducted to assess the efficacy and safety of tegase-
rod. Two of the studies had a fixed dose regimen
of 6 mg twice daily, while the third study used a
dose titration design. Efficacy was determined
based upon patient response to a specific test called
the Subject's Global Assessment of Relief and the
Subject's Global Assessment of Abdominal Pain
and Discomfort. A patient was considered a re-
sponder if they were assessed as being completely
relieved of symptoms for at least 2 of the 4 weeks
at each assessment, or if they were at least some-
what relieved for each of the previous 4 weeks. The
results are summarized in table 2. The differences
in response rates vs. placebo were greater at the end
of 4 weeks than at the end of 12 weeks. Tegaserod
produced a clinically effective means of reducing
constipation due to IBS.18'19
In another randomized, double blind, pla-
cebo-controlled trial, tegaserod was evaluated
against placebo for 12 weeks. Two hundred ninety
nine patients were randomized to 2 mg twice daily,
294 to 6 mg twice daily, and 288 to placebo. The
Subject's Global Assessment of Relief and the Sub-
ject's Global Assessment of Abdominal Pain and
Discomfort were used to determine efficacy. In fe-
males, the responder rates for the Subject's Global
Assessment of Relief at the end of 12 weeks were
37.7%, 38.9%, and 27.5% for the 2 mg, 6 mg, and

Pha rma Note Volume 18, Issue 3 December 2002


Volume 18, Issue 3 December 2002

Table 2. Percentage of patients responding to therapy, defined as symptoms completely relieved for 2 of 4 weeks, or
somewhat relieved for 4 weeks 18,19
End of 4 weeks (portion of responders) End of 12 weeks (portion of responders)
Tegaserod 6mg bid Placebo Difference (95% CI) Tegaserod 6mg bid Placebo Difference (95% CI)

1 31% 17% 14%(6-21%) 39% 28% 11% (3-20%)
2 35% 22% 13% (8-17%) 44% 39% 5% (0-10%)
3 34% 20% 14% (6-22%) 43% 38% 5% (-4-14%)

placebo groups respectively. The differences be-
tween the each group and placebo were statistically
significant (p=0.017 for the 2 mg and p=0.008 for 6
mg group after correcting for center effect). Similar
statistically significant results were seen in the
Subjetc's Global Assessment of Abdominal Pain
and Discomfort.22
In the premarketing clinical trials for
tegaserod, Novartis was unable to enroll enough
male patients to obtain the power to detect a statis-
tically significant difference, hence the indication
for women only. Currently, Novartis is studying
tegaserod's efficacy in male patients.

The recommended dosage for tegaserod is 6
mg twice daily before meals for 4 to 6 weeks. If the
patient responds to therapy at 4-6 weeks, an addi-
tional 4-6 weeks can be added. Tegaserod's effi-
cacy has not been studied in males, or in patients
for use longer than 12 weeks.

Adverse Events
Diarrhea, abdominal pain, headache, flatu-
lence, and fatigue were the most commonly re-
ported adverse events in phase III clinical trials.23
However, the only adverse events reported that
were statistically more significant than placebo
were diarrhea and headache.24 Table 3 summarizes
the percent of patients who experienced adverse
events compared to placebo in phase III clinical tri-
als. 1
Other adverse events reported in phase III
clinical trials include increase in abdominal sur-
gery, primarily cholecystectomies, hypotension,
angina pectoris, increased liver enzymes, and facial
edema. However, none of these were attributed to
tegaserod use.

Drug Interactions
In vitro drug-drug interaction data indicated
that tegaserod did not affect the CYP isoenzyme
system. As of now, tegaserod does not influence
the metabolism of other medications. Drugs that
potentially could interact with tegaserod include
pro-kinetic agents increasing the risk of diarrhea,
and antimuscarinics antagonizing the affects of
tegaserod. Tegaserod should not be used in combi-
nation with other GI motility altering medications
without careful monitoring.

Cost of Therapy
The retail cost for one month of therapy (60
tablets) of tegaserod 2 mg ranged from $154.78 to
$178.39, while a month supply of the 6 mg tablets
ranged from $156.36 to $178.39.

Serotonin modulators represent a new class
of medications that can be used to treat IBS symp-
toms. While these agents can be effective in the
treatment of symptoms associated with IBS, they
are not the first line agents, and should be consid-
ered once the patient has failed to respond to con-
ventional therapy.
Alosetron, a 5-HT3 receptor antagonist, has
been shown to be very efficacious in the treatment
of severe diarrhea predominant IBS in women that
have failed other therapies, but it must be moni-
tored diligently. Alosetron should be discontinued
in patients at the first sign of constipation or
ischemic colitis.
Tegaserod, a 5-HT4 receptor partial agonist,
has been shown to be efficacious in the treatment of
severe constipation predominant IBS in women at a
dose of 6 mg twice daily. Although efficacy has not
been established in males due to patient enrollment

PharmaNot Vlum 18 Isue3 Dcemer 00


Volume 18, Issue 3 December 2002

Table 3. Adverse events occurring in >1% of patients

A e E t Tegaserod 6mg bid Placebo
(n=1,327) (n=1,305)
Diarrhea 9% 4%
Abdominal pain 12% 11%
Nausea 8% 7%
Flatulence 6% 5%
Headache 15% 12%
Dizziness 4% 3%
Migraine 2% 1%
Accidental Trauma 3% 2%
Leg Pain 1% <1%
Back Pain 5% 4%
Arthropathy 2% 1%
* Statistically significant versus placebo

problems, no evidence exists to show that tegaserod
would not work in male patients. While tegaserod
has not yet been shown to cause such serious com-
plications as alosetron, it should also be monitored
carefully in all patients.

1. Patel RP, Petitta A, Fogel R, Peterson E, Zarowitz BJ.
The Economic Impact of Irritable Bowel Syndrome in a
Managed Care Setting. J Clin Gastroenterol 2002;35
2. De Ponti F, Tonini M. New Agents Targeting Serotonin
Receptor Subtypes. Drugs 2001; 61(3):317-332.
3. Thompson WG. Review Article: The Treatment of Irrita-
ble Bowel Syndrome. Aliment Pharmacol Ther 2002;
4. Talley NJ. Serotoninergic Neuroenteric Modulators. Lan-
cet 2001;358:2061-68.
5. Thompson WG, Longstreth GF, Drossman DA, Heaton
KW, Irvine EJ, Muller-Lissiner SA. Functional Bowel
Disease and Functional Abdominal Pain. Gut 1999;
6. Lotronex package insert, GlaxoSmithKline, 2002
7. FDA talk paper. Glaxo Wellcome Decides To Withdraw
Lotronex From The Market. November 28, 2000.
8. FDA talk paper. FDA Approves Restricted Marketing of
Lotronex. June 7, 2002.
9. D'Souza DL, Levasseur LM, Nezamis J, Robbins DK,
Simms L, Kock KM. Effects of Alosetron on the Pharma-
cokinetics of Alprazolam. J Clin Pharmacol. 2001;
10. CDER Drug Information. Patient-Physician Agreement
for Lotronex. www.fda.gov.
11. CDER Drug Information. Prescribing Program for
Lotronex: Physician Attestation of Qualifications and
Acceptance of Responsibilities. www.fda.gov.
12. CDER Drug Information. Medication Guide for Lotronex

Tablets (alosetron hydrochloride). www.fda.gov.
13. Camilleri M, Northcut AR, Kong S, Dukes GE, McSor-
ley D, Mangel AW. Efficacy and Safety of Alosetron in
Women with Irritable Bowel Syndome: a Randomized,
Placebo-controlled Trial. Lancet 2000; 355:1035-40.
14. Watson ME, Lacey L, Kong S, Northcut AR, McSorley
D, Hahn B, Mangel AW. Alosetron Improves Quality of
Life in Women With Diarrhea-Predominant Irritable
Bowel Syndrome. Am J Gastroenterol 2001;96:455-459.
15. Camilleri M, Mayer EA, Drossman DA, Heath AT,
Dukes GE, McSorley D, et al. Improvement in Pain and
Bowel Function in Female Irritable Bowel Patients with
Alosetron, a 5-HT3 Receptor Antagonist. Aliment Phar-
macol Ther 1999;13:1149-1159.
16. Wolfe SG, Chey WY, Washington MK, Harding J, Heath
AT, McSorley D, et al. Tolerability and Safety of Alose-
tron During Long-Term Administration in Female and
Male Irritable Bowel Syndrome Patients. Am J Gastroen-
terol 2001;96:803-811.
17. FDA Talk Paper FDA Approves first treatment for
women with constipation-predominant irritable bowel
syndrome. July 24, 2002 www.fda.gov.
18. Zelnorm package insert. Novartis Pharmaceuticals Cor-
poration 2002.
19. Camilleri M. Review Article: Tegaserod. Aliment Phar-
macol Ther; 15:277-289.
20. Appel-Dingemanse S, Horowitz A, Campestrini J, Os-
borne S, Mcleod J. The Pharmacokinetics of the Novel
Promotile Drug, Tegaserod, are Similar in Healthy Sub-
jects-Male and Female, Elderly and Young. Aliment
Pharmacol Ther 2001;15:937-944
21. Scott W, Perry LM Drugs 1999;58:491-6.
22. Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F,
Pecher E Nault B et al. Tegaserod, a 5-HT4 Receptor Par-
tial Agonist, Relieves Symptoms in Irritable Bowel Syn-
drome with Abdominal Pain, Bloating, and Constipation.
Aliment Pharmacol Ther 2001: 15:1655-1666.
23. Fidelholtz J, Smith W, Rawls J, Shi Y, Zack A, Ruegg P
et al. Safety and Tolerability of Tegaserod in Patients
with Irritable Bowel Syndrome and Diarrhea Symptoms.
Am J Gastroenterol 2002;97:1176-1181.
24. Lacy BE, Yu S. Tegaserod, A New 5-HT4 Agonist. J Clin
Gastroenterol 2002;34(1):27-33.
25. Prices based on 4 community pharmacies in the Gaines-
ville, FL area.

Hepsera (adefovir dipivoxil) is an acyclic
nucleotide analog recently approved for the
treatment of chronic hepatitis B in adults
with evidence of active viral replication and
either evidence of persistent elevations in
serum aminotransferases or histologically
active disease. The usual adult dose is 10mg
once daily; however, dosage adjustment is
necessary in patients with renal dysfunction.

Pha rma Note Volume 18, Issue 3 December 2002


Volume 18, Issue 3 December 2002


Amy J. Baker, Pharm.D. Candidate

The treatment of asthma is not stagnant and
unchanging. New information is constantly evolv-
ing as studies are conducted, reinforcing or dis-
proving previous ideas and treatment strategies. Re-
sults from additional research have become avail-
able since 1997 when the previous Guidelines for
the Diagnosis and Management of Asthma were
published.1 The National Asthma Education and
Prevention Program Expert Panel Report (NAEPP
EPR) released the Update on Selected Topics 20022
in June of this year, which is an up-to-date report of
recommendations on the diagnosis and manage-
ment of asthma.
The objective of this article is to compare
the differences between the 1997 guidelines and the
2002 update. Unfortunately, the complete guide-
lines, with references to the actual studies recom-
mendations are based on, will not be available until
2003. For practical purposes, the update is divided
into three categories: medication, monitoring and


Long-Term Management of Asthma in Children
Under the Age of Five
The update discusses changes in the re-
quirements for initiation of long-term therapy in the
treatment of asthma in infants and children younger
than five years of age. The following summarizes
the differences between the 1997 guidelines and the
2002 update.
1997 Guidelines
Long-term treatment should be initiated in
infants and young children requiring symptomatic
treatment more than two times per week or in chil-
dren experiencing severe exacerbations less than
six weeks apart.

2002 Update
Initiation of long-term asthma treatment
should be considered in infants and children with
more than three episodes of wheezing in the past
year lasting more than one day AND the child's
sleep having been affected AND the child having a
high risk of developing asthma (defined as parental
history of asthma OR physician diagnosed atopic
dermatitis OR any two of the following: physician
diagnosed allergic rhinitis, wheezing apart from
colds, or peripheral blood eosinophilia). It is still
recommended to initiate long-term treatment in in-
fants and young children requiring symptomatic
treatment more than two times per week OR in
children experiencing severe exacerbations less
than six weeks apart.

Recommendationsfor when to begin long-term
asthma therapy have been broadened to in-
clude more conditions allowingfor more chil-
dren and infants to benefit from treatment.

Combination Therapy
Previously, when long-term therapy was
initiated, inhaled corticosteroids were used as the
treatment of choice. If asthma symptoms were not
controlled, a long-acting beta-2 agonist was added.
Initiating therapy with the combination of inhaled
corticosteroids and a long-acting beta-2 agonist is
now recognized as a more effective approach. One
hundred thirty-six patients were enrolled in a ran-
domized, double-blind, double-dummy, parallel
group clinical trial comparing salmeterol 21 ug,
fluticasone 44 ug, fluticasone 110 ug, salmeterol 21
ug PLUS fluticasone 44 ug, salmeterol 21 ug PLUS
fluticasone 110 ug, and placebo. Results showed
the greatest improvement in asthma signs and
symptoms in the combination therapy groups.
Forced expiratory volume (FEV) was significantly
improved for the higher-dose fluticasone treatment
group and for both of the combination treatment
groups when compared to placebo. In addition, the
FEV significantly improved more in the combina-
tion treatment groups when compared to the mono-
therapy group. A significant decrease in patient re-
ported asthma symptoms and number of nighttime
awakenings and a significant increase in the num-

Ph ra ot Vlue 8,Isue3 ecmbr 00


Volume 18, Issue 3 December 2002

ber of days without asthma symptoms was ob-
served in the combination treatment groups com-
pared to the monotherapy treatment groups. This
study supports the recommendation of initiating
long-term therapy with the combination of inhaled
corticosteroids and long-acting beta-2 agonists.3

Combination Therapy in Infants and Children
Under the Age of Five
The preferred combination therapy has been
redefined for the treatment of moderate persistent
asthma in infants and children under the age of five.
Low dose inhaled corticosteroids used in conjunc-
tion with long-acting inhaled beta-2 agonists is now
the treatment of choice.
1997 Guidelines
The options for treatment of moderate per-
sistent asthma in this age group include either me-
dium-dose inhaled corticosteroids OR medium-
dose inhaled corticosteroids used concomitantly
with either nedocromil or theophylline. No prefer-
ence was given to any of the combinations of treat-
2002 Update
The preferred treatment of moderate asthma
in this age group is low-dose inhaled corticoster-
oids used with long-acting inhaled beta-2 agonists
OR medium-dose inhaled corticosteroids alone.

Based on evidence from studies, the NAEPP
EPR now recommends initiation of combina-
tion therapy in the treatment of moderate
persistent asthma in infants and children un-
der the age of five i/ ith low-dose inhaled cor-
ticosteroids and long-acting beta-2 agonists.

Combination Therapy in Adults and Children
Over the Age of Five
The recommendation for combination ther-
apy in the treatment of moderate persistent asthma
in adults and children over the age of five has also
been redefined. The options remain the same but
the combination of inhaled corticosteroids used in
conjunction with long-acting beta-2 agonists has
now become the treatment of choice.

1997 Guidelines
The options for treatment of moderate per-
sistent asthma include either medium dose inhaled
corticosteroids OR low to medium dose inhaled
corticosteroids combined with one of the following:
a long-acting beta-2 agonist OR sustained release
theophylline OR long-acting beta-2 agonist tablets.
No preference of treatment was noted in the 1997
2002 Update
The preferred treatment for moderate persis-
tent asthma is low to medium dose inhaled corticos-
teroids AND a long-acting inhaled beta-2 agonist.
The second-line treatment option is either medium
dose inhaled corticosteroids as monotherapy OR
the combination of low to medium dose inhaled
corticosteroids with either a leukotriene modifier
OR theophylline.

Based on evidence from studies, the NAEPP
EPR now recommends initiation of combina-
tion therapy in the treatment of moderate per-
sistent asthma in adults and children over the
age offive i/ ith low-dose inhaled corticoster-
oids and long-acting beta-2 agonists.

Long-Term Effects of Inhaled Corticosteroids
The previous guideline's statement that
"Inhaled corticosteroids improve health outcomes
for children with mild or moderate persistent
asthma, and the potential but small risk of delayed
growth is well balanced by their effectiveness" has
not changed in the 2002 guidelines but is now sup-
ported with more evidence. When the previous
guideline was published, only short-term studies
had been conducted. A multi-centered, double-
blind, double-placebo, randomized controlled clini-
cal trial followed 195 children for one year and
found that beclomethasone (two puffs inhaled four
times daily) did cause a decrease in growth. The
slowed growth rate was found to affect pre-pubertal
males more than females.4 In a separate double-
blind, placebo-controlled randomized clinical trial,
94 children between the ages of seven and nine
were evaluated for the effect of beclomethasone on
growth. This trial, which was conducted over 7
months, found a significant decrease in growth in

Pha rma Note Volume 18, Issue 3 December 2002


Volume 18, Issue 3 December 2002

both males (p<0.001) and females (p<0.008) of one
centimeter. This study concluded that the growth
did not catch up following a four month wash-out
period (p=0.45).3 Two other studies did not find a
detrimental effect on growth. The first study fol-
lowed fifty-eight children for 4.9 years to evaluate
the impact of beclomethasone and budesonide on
growth. This study found a difference in growth
based on asthma severity (p=0.003) and not based
on treatment group (95% confidence interval of -4.2
to +2.9).6 The second study was a meta-analysis of
21 trials comprising 810 patients. This analysis
found "a significant tendency for beclomethasone
to be associated with attaining normal stat-
ure" (p=2.17 E-13).7 However, long-term effects of
inhaled corticosteroids on growth rates were not es-
tablished in any of these trials.
More long-term studies have now been con-
ducted evaluating the effect of inhaled corticoster-
oids on growth in children. A prospective clinical
trial followed 211 children over 9.2 years to deter-
mine the effects of budesonide on growth. This trial
found a significant decrease in growth by one centi-
meter during the first year of treatment (p<0.001);
however, final adult height was reached in most pa-
tients (p<0.001). Also, no association of decreased
growth based on gender (p=0.3) was found.8 In ad-
dition, studies show no harmful effects on bone
density and no increase in the formation of cataracts
or glaucoma.9 Finally, inhaled corticosteroids were
shown to have only a minor, if any, effect on the
hypothalamic-pituitary-adrenal (HPA) axis func-
tion. (The studies these statements are based on
will not be released until the official publication of
the guidelines in 2003).

Use of Antibiotics
The 2002 guidelines are consistent with the
1997 guidelines stating that asthma is an inflamma-
tory disease and antibiotics are not recommended as
a treatment option. Antibiotics are only to be used
in patients with other conditions such as fever or
suspected underlying bacterial infection.

It is still encouraged to use written action
plans in patients with moderate or severe persistent
asthma and in patients with a history of severe
asthma exacerbations. It is also still recommended

to utilize peak flow monitoring as the basis for the
written plan.

The NAEPP EPR has reevaluated and up-
dated the previous guideline's statements regarding
the progression of asthma in children between the
ages of five and twelve.
1997 Guidelines
Early treatment of mild persistent or moder-
ate persistent asthma in children between the ages
of five and twelve may help slow the progression of
the disease process.
2002 Update
Treatment of mild persistent or moderate
persistent asthma in children between the ages of
five and twelve may provide asthma control but
symptoms and airway hyperresponsiveness may re-
turn upon discontinuation of treatment.

NAEPP EPR now states that treatment of mild
persistent and moderate persistent asthma in
children between the ages offive and twelve
does help control symptoms but does not cure
the underlying disease. The symptoms of
asthma will return upon stopping treatment.

The major updates to the 1997 Guidelines
for the Diagnosis and Management of Asthma have
been released. The primary categories of changes
include medication usage, monitoring and preven-
tion. Within the medication category the following
changes were made: (1) when to initiate long-term
treatment in infants and children, (2) use of low-
dose inhaled corticosteroids in conjunction with
long-acting beta-2 agonists as the combination ther-
apy of choice in moderate persistent asthma, (3) in-
creased evidence documenting the safety of inhaled
corticosteroids, and (4) the inappropriateness of us-
ing antibiotics in the treatment of asthma. No
changes were made in the category of monitoring;
it is still recommended to utilize peak flow moni-
toring and written action plans in the treatment of
moderate or severe persistent asthma. In the pre-
vention category, it is now realized that early initia-

Pha ma Nte Vlume18, ssue3 Deembe 200


Volume 18, Issue 3 December 2002

tion of treatment in mild to moderate persistent
asthma in children aged five to twelve will not cure
the disease, only maintain control of symptoms.
The publication of the complete 2002
Asthma Guidelines, including references to the
studies the recommendations are based on, should
be released sometime in 2003. Refer to www.nhlbi.
nih.gov for further information.

1. The National Institutes of Health/National Heart, Lung,
and Blood Institute. Guidelines for the Diagnoses and
Management of Asthma-Expert Panel Report 2.
2. The National Institutes of Health/National Heart, Lung,
and Blood Institute. NAEPP Expert Panel Report: Guide-
lines for the Diagnoses and Management of Asthma-
Update on Selected Topics 2002.
3. Pearlman DS, Stricker W, Weinstein S, et al. Inhaled Sal-
meterol and Fluticasone: a Study Comparing Monother-
apy and Combination Therapy is Asthma. Ann Allergy
Asthma Immunol 1999 Mar;82(3):257-65.
4. Tinkelman DG, Reed CE, et al. Aerosol Beclomethasone
Dipropionate Compared with Theophylline as Primary
Treatment of Chronic, Milt to Moderately Severe Asthma
in Children. Pediatrics 1993 Jul;92(1):64-77.
5. Doull IJ, et al. Growth of Prepubertal Children with Mild
Asthma Treated with Inhaled Beclomethasone Dipropion-
ate. Am JRespir Crit Care Med 1995 Jun; 151(6):1715-9.
6. Ninan TK, et al. Inhaled Corticosteroid Treatment, and
Growth. Arch Dis Child 1992 Jun;67(6):703-5.
7. Allen DB, Mullen M, Mullen B. A Meta-Analysis of the
Effect of Oral and Inhaled Corticosteroids on Growth. J
Allergy Clin Immunol 1994;93(6):967-76.
8. Agertoft L, Pdersen S. Effect of Long-Term Treatment
with Inhaled Budesonide on Adult Height in Children
with Asthma. NEngl JMed 2000 Oct 12;343(15):1064-9.
9. Li JT, Goldstein MF, Gross GN, Noonan MJ, Weisberg S,
Edwards L et al. Effects of Fluticasone Propionate, Triam-
cinolone Acetonide, Prednisone, and Placebo on the Hy-
pothalamic-Pituitary-Adrenal Axis. J Allergy Clin Immu-
nol 1999 Apr;103(4):622.

DuacT Topical Gel (clindamycin 1%/
benzoyl peroxide 5%) is a recently approved
antibacterial/keratolytic for the topical
treatment of inflammatory acne vulgaris. In
adults and children 12 years of age or older,
it should be applied once daily in the evening
after washing and pat drying the face.

New Indications
Altocor Primary prevention of CHD in
patients without CV symptoms
who have average to moderately
elevated Total-C and LDL-C and
below average HDL-C.
Avapro Diabetic nephropathy in patients
with hypertension.
Cancidas Eesophageal candidiasis.
Cozaar Diabetic nephropathy in patients
with hypertension.
Valtrex Cold sores in healthy adults.

New Formulations
Prevacid By the end of the year it will be
available as delayed-release
orally disintegrating tablets in 15
mg and 30 mg strengths.
Skelaxin An new 800 mg tablet was just
approved for relief of discomforts
associated with acute, painful
musculoskeletal conditions.

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

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor



Volume 18, Issue 3 December 2002

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