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XOPENEX: THE BEGINNING
OF A NEW TREND IN
PHARMACEUTICS OR ALL
HYPE ?

Keith C. Lowe, Pharm.D. Candidate



Asthma is a chronic inflammatory disorder
of the airways in which many cells and cellular ele-
ments play a role.1 This inflammation causes recur-
rent episodes of wheezing, breathlessness, chest
tightness, and coughing, particularly at night or in
the early morning. These episodes are characterized
by reversible airflow obstruction. In the United
States more than 11 million people reported an
asthma attack in the year 2000, and more than 5
percent of all children younger than age 18 reported
having an attack. In 1999, asthma was responsible
for 2 million emergency department visits, 478,000
hospitalizations, and 4,426 deaths.2
In all forms of asthma, there is some degree
of airway inflammation. This inflammation is a re-
sult of the infiltration of the airway by inflamma-
tory cells (i.e. eosinophils, activated T cells, mast
cells, macrophages, etc.) that cause denudation of
the epithelium, deposition of collagen, and hyper-
plasia and hypertrophy of bronchial smooth muscle.
Immunoglobulin E (IgE) binds to mast cells and
basophils, signaling the release of histamine and
leukotrienes, which results in bronchoconstriction
during the acute phase. Mast cells produce inter-
leukin (IL)-1, IL-2, IL-3, IL-4, and IL-5, granulo-
cyte-macrophage colony-stimulating factor (GM-


CSF), interferon-gamma (IF-y), and tumor necrosis
factor-alpha (TNF-a) each of which contributes to
acute and chronic inflammation in asthmatic pa-
tients.
The initial goals in the treatment of acute
asthma are to rapidly reverse airflow obstruction
and to correct hypoxemia.3 Systemic corticosteroids
and aggressive use of inhaled 32-agonists continue
to be the cornerstone of therapy for acute exacerba-
tions. Xopenex (levalbuterol) is the (R)-
enantiomer of racemic albuterol and is one of the
first in a new trend of pharmaceuticals where a spe-
cific stereoisomer is isolated and marketed because
it has the potential to be more efficacious or safer
than the racemic mixture. Levalbuterol received
FDA approval in 1999 for the prevention and treat-
ment of bronchospasm in adults and adolescents 12
years of age and older with reversible, obstructive
airway disease. In 2002, levalbuterol received ap-
proval for use in children 6 years of age or older.4
This review will evaluate the evidence supporting
levalbuterol's efficacy and safety for the treatment
of reactive airway disease.

Mechanism of Action
Levalbuterol activates 32-adrenergic recep-
tors on airway smooth muscle, leading to the acti-



INSIDE THIS ISSUE:
XOPENEX: THE BEGINNING OF A NEW
TREND IN PHARMACEUTICS OR ALL
HYPE


mm


A9 PharmaNote


VOLUME 20, ISSUE 8 MAY2005
Ti MA 20


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Table 1. Mean (SD) values for pharmacokinetic parameters in healthy adults.5


Single Dose
Levalbuterol
1.25 mg


Racemic albuterol 2.5


Cumulative Dose
Levalbuterol
Sm5 m


Racemic
albuterol 10mg


Cmax (ng/ml) 1.1(0.45) 0.8 (0.41) 4.5 (2.20) 4.2 (1.51)
Tmax (h)* 0.2 (0.17, 0.37) 0.2 (0.17, 1.50) 0.2 (-0.18f, 1.25) 0.2 (-0.28", 1.00)
AUC (ng-h/ml) 3.3 (1.58) 1.7 (0.99) 17.4 (8.56) 16.0 (7.12)
T1/2 (h) 3.3 (2.48) 1.5 (0.61) 4.0 (1.05) 4.1 (0.97)

Tma denotes time to maximum serum concentration. *Median (Min, Max) reported for Tma; tA negative Tmax indicated Cmax occurred between first and last
nebulizations.


vation of adenylate cyclase and to an increase in the
intracellular concentration of cyclic adenosine mo-
nophosphate (cAMP).4 This increase in cAMP
leads to the activation of protein kinase A, which
inhibits the phosphorylation of myosin and lowers
intracellular ionic calcium concentrations, resulting
in relaxation of smooth muscle in the airways, from
the trachea to the terminal bronchioles. Leval-
buterol also acts as a functional antagonist by relax-
ing the airways upon provocation by any number of
potential spasmogens, thus protecting against all
bronchoconstrictor challenges.

Pharmacokinetics
The inhalation pharmacokinetics of leval-
buterol were investigated in a double-blind, cross-
over, randomized controlled trial in adults and ado-
lescents 12 years of age or older.5 Thirty healthy
adults received a single dose of 1.25 mg and a cu-
mulative dose of 5 mg of levalbuterol and a single
dose of 2.5 mg and a cumulative dose of 10 mg of
racemic albuterol by nebulization. The drug was
administered every 30 minutes for a total of four
doses. The pharmacokinetic parameters were deter-
mined by noncompartmental analysis and model-
fitting. (Table 1) The maximum drug concentration
(Cmax) and area under the curve (AUC) of (R)-
albuterol were similar for both levalbuterol and ra-
cemic albuterol.
The pharmacokinetic parameters of (R)-
albuterol and (S)-albuterol in children, 6 to 12
years of age, with asthma were obtained using
population pharmacokinetic analysis.6 In children,
the AUC and Cmax of (R)-albuterol following ad-
ministration of 0.63 mg levalbuterol inhalation so-
lution were similar to that of 1.25 mg of racemic


albuterol. (Table 2) Following administration of
the same dose of 0.63 mg of levalbuterol to chil-
dren and adults, the predicted Cmax of (R)-albuterol
in children was similar to that in adults, while the
predicted AUC was 1.5-fold higher than that in
adults. This data supports the use of lower doses in
children (6-11 years of age) compared to adults and
adolescents.
A comparison of the most clinically rele-
vant inhalation pharmacokinetics demonstrates that
there is essentially no difference in onset and dura-
tion of action between the two formulations.7
(Table 3)

Pharmacodynamics
In vitro experiments have compared the
binding of (R)-, (S)-, and racemic albuterol to P1-
and 32-adrenergic receptors in human prostate
cells.8 The results show that (R)-albuterol has a
100-fold greater binding affinity for both types of
adrenergic receptors than (S)-albuterol. It has long
been thought that (S)-albuterol was pharmacologi-
cally inert. This has been disputed given that this
assertion is based upon in vitro studies using recep-
tor binding and functional assays, while little is
known of the in vivo effects in asthmatic individu-
als. In isolated smooth muscle cells that (S)-
albuterol can promote a cellular influx of calcium.
It can also oppose the dose-dependent decrease in
calcium that is produced by (R)-albuterol.9 Other
studies have demonstrated that (S)-albuterol de-
creases the expression and activity of the bron-
chodilatory pathway involving Gs proteins in vitro
and also activates pro-inflammatory pathways in-
volving phosphotidylinositol 3'-OH (PI3) kinase
and nuclear factor KB (NF-xB).10 (R)-albuterol in-


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Table 2. (R)-albuterol exposure in adults and pediatric subjects (6-11 years of age).6
Children 6-11
years of age Adults >12 y


Levalbuterol
0.31 mg


Levalbuterol
0.63 mg


Racemic
albuterol
1.25 mg


ears of age


Racemic
albuterol Le
2.5 mg


evalbuterol
0.63 mg


Levalbuterol
1.25mg


Cmax (ng/ml) 0.303 0.521 0.553 1.08 0.56* 1.1l
AUC (ng-h/ml) 1.36 2.55 2.65 5.02 1.65* 3.3"

* The values are predicted assuming linear pharmacokinetics; tThese data were obtained from Table 1


hibits airway epithelial cytokine, chemokine and
nitric oxide release in vitro, while (S)-albuterol can
increase the activity of these mediators, suggesting
a possible pro-inflammatory effect.11 Some in vitro
studies have suggested that (S)-albuterol can en-
hance the contractile effect of spasmogens, while
(R)-albuterol can inhibit direct and indirect spas-
mogen-induced contractions.12 Other studies have
suggested that there are dose-related 12 responses
(i.e. tremor, heart rate, plasma potassium) for (R)-
albuterol and racemic albuterol, while (S)-albuterol
was similar to placebo.13 These differences suggest
that the (R)-isomer is responsible for the bulk of the
pharmacological activity of albuterol.

Clinical Trial Data
The first large scale randomized, double-blind, par-
allel-group trial enrolled 362 patients with moder-
ate to severe asthma to assess the efficacy and
safety of levalbuterol.14 Eligible patients were non-
smoking males or females 12 years of age or older
who had at least a 6-month history of chronic stable
asthma (as defined by the American Thoracic Soci-
ety) requiring pharmacotherapy. Moderate to severe
asthma was defined as an FEV1 between 45% and
70% of the predicted normal value. Patients were
allowed to take other medications for asthma or
allergic rhinitis if taken as part of a stable regimen;
however, this therapy was withheld for an appropri-
ate washout period prior to study visits. All patients
were provided with a racemic albuterol metered
dose inhaler (MDI) to be used on an as-needed ba-
sis for relief of acute asthma symptoms. The mean
age of study participants was 36.5 years and 60%
were female. Patients were randomly assigned to
receive one of 5 treatments 3 times daily for 4
weeks: 0.63 mg levalbuterol, 1.25 mg levalbuterol,
1.25 mg racemic albuterol, 2.5 mg racemic al-
buterol, or placebo. All active treatment arms re-


sulted in clinically significant improvement (>15%
improvement in FEVi) immediately after nebuliza-
tion. The levalbuterol treatment groups had a sig-
nificantly greater improvement in mean peak FEVI
than the racemic albuterol groups after the first
dose (P=0.03), but not at week 4 (P=0.13). After
both the first dose and 4 weeks of treatment, the
greatest peak improvement and longest duration of
improvement were observed for patients treated
with levalbuterol 1.25 mg. The weakest bronchodi-
lator effect and the shortest duration of action were
seen in patients receiving racemic albuterol 1.25
mg, which was not significantly better than placebo
at week 4. All other active treatment arms were sig-
nificantly better than placebo at both week 0 and
week 4 (P<0.01). Overall, the rank order of efficacy
regarding change in FEV1 for all analyses was as
follows: 1.25 mg levalbuterol > 0.63 mg leval-
buterol =2.5 mg racemic albuterol > 1.25 mg race-
mic albuterol = placebo. The authors concluded
that levalbuterol is approximately 4 times more po-
tent than the 2.5 mg dose of racemic albuterol ad-
ministered in this study. The study medications
were well tolerated with no significant differences
in adverse effects across treatment groups.
A large multicenter, randomized, double-
blind, controlled trial attempted to establish the ef-
ficacy of levalbuterol in 338 children aged 4 to 11
years of age.6 Selection criteria included a diagno-
sis of at least mild asthma for >60 days before
screening and baseline FEV1 within 40% to 85% of
predicted with >15% reversibility using racemic
albuterol. All eligible patients received 21 days of
treatment with levalbuterol 0.31 mg, levalbuterol
0.63 mg, racemic albuterol 1.25 mg, racemic al-
buterol 2.5 mg, or placebo each administered 3
times daily. All active treatments produced signifi-
cant improvement in FEV1. (Table 4) The effect of
levalbuterol 0.31 mg on FEV1 was not signifi-


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Table 3. Comparison of inhalation pharmacokinetics for levalbuterol and racemic albuterol7
Onset of Action (mins)* Time to peak effect (hrs) Duration of action (hrs)
Levalbuterol 0.63 mg 17 1.5 5
Levalbuterol 1.25 mg 10 1.5 6
Racemic albuterol 5-15 0.5-2.0 2-6

Defined as >15% increase in forced expiratory volume in one second (FEV1)


cantly different than that of racemic albuterol 2.5
mg at either day 0 or day 21. Clinically significant
changes in FEV1 occurred immediately after nebu-
lization on days 0 and day 21 for all groups except
placebo and racemic albuterol 1.25 mg. Leval-
buterol 0.31 mg was the only treatment not differ-
ent from placebo with regards to changes in ven-
tricular heat rate, QTc interval, and serum glucose.
The authors concluded that levalbuterol is 4- to 8-
fold more potent than racemic albuterol and exhib-
its a more favorable safety profile.
Considerable debate has emerged regarding
the results of these studies.15 The 4 to 8 fold differ-
ence in potency between levalbuterol and racemic
albuterol hass not been universally agreed upon.14
These trials were designed to assess efficacy and
safety compared to placebo, but were not suffi-
ciently powered to compare levalbuterol with race-
mic albuterol. Doses were near the top of the dose-
response curves, and there were no statistically sig-
nificant differences between doses of the same drug
or between different drugs. Conclusions on the
relative efficacy of levalbuterol versus racemic al-
buterol cannot be made due to the lack of statistical
power to make this comparison, the lack of a clear
dose-response relationship in the active treatment
arms, and the presence of an inverse dose-response
for levalbuterol. Chowdhurry is not alone as several
other authors have voiced concern.16,17 One group
noted that the authors of previous studies failed to
address the fact that the (S)-isomer is inactive, and,
that in fact previous estimates of the leval-
buterol:albuterol potency have been flawed.17 In
addition to these concerns, there were no signifi-
cant differences in the peak change in FEV1 after
doubling the dose of either levalbuterol or racemic
albuterol; therefore, it is not possible to draw con-
clusions related to relative efficacies of levalbuterol
versus racemic albuterol.
Attempts have been made to determine
whether or not the in vitro binding assays actually


result in clinically significant differences in asth-
matics. Lotvall et al sought to compare the bron-
chodilating and systemic effects of (R)-albuterol
and racemic albuterol in a crossover, double-blind,
placebo-controlled fashion.18 Twenty-two patients
with a documented history of asthma were random-
ized to receive (R)-albuterol, (S)-albuterol, racemic
albuterol, or placebo for one day in successive fash-
ion. Patients were administered the following
doses: (R)-albuterol or (S)-albuterol 6.25, 12.5,
25, 50, 100, 200, 400, 800, and 1600 ag; racemic
albuterol 12.5, 25, 50, 100, 200, 400, 800, 1600,
and 3200 gg. Both (R)-albuterol and racemic al-
buterol produced significant and dose-dependent
increases in FEV1. There was no plateau at the
doses tested. Compared with placebo, (S)-albuterol
did not show any consistent effect on FEV1. At
higher doses of (R)-albuterol (>200 ag) and race-
mic albuterol (>400 ag) there were dose-dependent
increases in heart rate and decreases in serum po-
tassium. It was determined that (R)-albuterol and
racemic albuterol have a 2:1 potency ratio for im-
provement in FEV1 in asthmatic patients and that
that (R)-albuterol is the pharmacologically active
enantiomer. Since half the dose of (R)-albuterol
compared with racemic albuterol was required to
reach similar bronchodilation, as well as similar
systemic side effects on heart rate and plasma po-
tassium level, this tends to support the argument
that the (S)-component of racemic albuterol is inert
and clinical activity is a function of the (R)-
enantiomer.
Recent studies have evaluated the outcome
of acute attacks of asthma or COPD following
treatment with levalbuterol. A retrospective chart
review was performed by Truitt et al. to determine
clinical efficacy, patient outcomes, and medical
costs in hospitalized patients treated with leval-
buterol compared to those treated with racemic al-
buterol.19 The length of hospital stay in the leval-
buterol group was approximately one day less than


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Table 4. Airway function measurements.6
Levalbuterol Levalbuterol Racemic Racemic
Placebo 0.31 mg 0.63 mg 1.25 mg 2.5 mg
Change in FEV1 (n=65) (n=70) (n=70) (n=67) (n=66) P value
Day 0
Median peak change (%) 16.0 27.0* 25.4* 24.2* 26.7* <0.001
Median time to peak change (%) 118 75* 83* 93* 90* <0.001
Median change (%), time 0 2.0 19.0* 18.1* 12.4* 15.6* <0.001
Response (%) at time 0 12.3 62.9*" 56.5* 41.8* 54.6* <0.001
Day 21
Median peak change (%) 17.9 24.9* 25.7* 22.3* 27.6* 0.02
Median time to peak percent (%) 97 77* 77* 75* 86* <0.001
Median change (%), Time 0 7.3 17.4* 15.9* 14.4* 16.6* <0.001
Response (%) at 6ime 0 31.2 56.3* 55.2* 47.6* 54.2* 0.02


* P<0.5 vs. placebo; t P<0.05 vs. racemic albuterol 1.25 mg; f Response defined as an improvement of-
completed immediately after nebulization. P-value denotes treatment versus placebo

those treated with racemic albuterol, and leval-
buterol-treated patients required significantly fewer Adverse Effe
treatments with a P-agonist or ipratropium than did Levall
patients treated with racemic albuterol. Signifi- atically colle
cantly more patients were readmitted within 30 events in adult
days of discharge in the racemic albuterol group The events o
compared with the levalbuterol group. Those ment arms. O
treated with levalbuterol had a lower mean total ness, headac
cost of nebulizer therapy and lower mean total hos- medications v
pital costs per patient when compared to racemic The f
albuterol. Lastly, regression analysis indicated that ered potential
levalbuterol was associated with a length-of-stay in less than 2
savings of 0.91 days, a total cost savings of $556, EKG changes
and a decrease in the likelihood of hospital read- diarrhea, dry
mission of 67%. Results from this trial must be in- enteritis, nau
terpreted in the context of the known limitations of myalgia, anxi
retrospective chart reviews, itching.
The potential of levalbuterol to prevent hos-
pitalizations in the acute management of asthma Dosage and
exacerbations was explored in randomized, double- The r
blind, placebo controlled fashion.20 Patients 1-18 buterol for p
years of age who presented to the emergency de- 0.63 mg admi
apartment in an urban tertiary care children's hospi- zation.4 Thos
tal were considered eligible for randomization. A whose respor
total of 482 patients were selected to receive either increased dos
2.5 mg of racemic albuterol or 1.25 mg of leval- tients receivil
buterol every 20 minutes, up to a maximum of six for systemic
doses. The hospitalization rate was significantly efficacy, and
lower in the levalbuterol group than the racemic for nebulizati
group (36% vs. 45%, respectively, P=0.02) while and efficacy i
the hospital length of stay was not significantly dif- using the PA]
ferent between the treatment arms. ers. Safety an


15% from baseline FEVi: Time 0 is the first FEV1,


cts
)uterol's pivotal clinical trial system-
;cted data on drug-related adverse
Its and adolescents.14 (Tables 5 and 6)
occurred at a similar rate across treat-
ther adverse events included nervous-
he, and tremor. Overall, the study
vere well tolerated.
allowing are adverse events, consid-
ly related to levalbuterol that occurred
% of patients: chills, pain, chest pain,
, hypertension, hypotension, syncope,
mouth, dry throat, dyspepsia, gastro-
sea, lymphadenopathy, leg cramps,
ety, insomnia, paresthesia, and ocular


Administration
recommended starting dose of leval-
atients 12 years of age and older is
nistered every 6 to 8 hours by nebuli-
e with more severe asthma or those
nse is insufficient may benefit from an
e of 1.25 mg three times a day. Pa-
ng higher doses should be monitored
adverse effects. Drug compatibility,
safety when mixed with other drugs
on has not been established. Safety
have been established in clinical trials
RI LC Jet and PARI LC Plus nebuliz-
id efficacy in other nebulizer systems


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Table 5. Potential drug-related adverse events.4t
Levalbuterol (n=145)


Racemic albuterol (n=142)


0.63 mg


No adverse effects (%)
Asthma*
Asthma increase*

Nervousness

Tremor
Headache

Tachycardia

Leg cramps
Anxiety
Dizziness


12 (6.7)
5 (6.9)

1(1.4)
2 (2.8)
0 (0.0)

3 (4.2)
2 (2.8)
0 (0.0)

0 (0.0)
1(1.4)


1.25 mg


23 (31.5)
4 (5.5)

3 (4.1)
7 (9.6)
5 (6.8)

4 (5.5)
2 (2.7)
2 (2.7)

2 (2.7)
2 (2.7)


1.25 mg


14 (20.6)
5 (7.4)

2 (2.9)
3 (4.4)
0 (0.0)

2 (2.9)
0 (0.0)
0 (0.0)

0 (0.0)
0 (0.0)


2.5 mg


20 (27.0)
6(8.1)

2 (2.7)
6(8.1)
2 (2.7)

2 (2.7)
2 (2.7)
0 (0.0)

0 (0.0)
0 (0.0)


Placebo (n=75)
14 (18.7)
7 (9.3)

2 (2.7)
0 (0.0)
0 (0.0)

3 (4.0)
0 (0.0)
1 (1.3)

0 (0.0)
0 (0.0)


*Undefined. T Events listed are those reported by 2% or more of patients in any treatment group.


has not been established.
The recommended dosage of levalbuterol
for patients 6-11 years of age is 0.31 mg adminis-
tered three times daily, by nebulization. In children,
routine dosing should not exceed 0.63 mg three
times a day. Maximum daily dosage should not ex-
ceed 3.75 mg per day via oral inhalation in adults
and adolescents 12 years of age or older, or 1.89
mg per day for children 6-11 years of age. The
safety and efficacy of levalbuterol in children less
than 6 years of age has not been determined.

Drug Interactions
Other short acting sympathomimetic bron-
chodilators and epinephrine should be used with
caution with levalbuterol.4 0-adrenergic receptor
blocking agents can antagonize the pulmonary ef-
fects of P-agonists or precipitate bronchospasm.
Patients with asthma should not be treated with 3-
blockers unless there are compelling indications,
such as post myocardial infarction or heart failure.
If a P-blocker must be used, a cardioselective agent
(eg, metoprolol, atenolol, bisoprolol) is preferred.
Diuretics (non-potassium sparing) administered
along with levalbuterol may potentiate alterations
in potassium homeostasis (i.e., hypokalemia); the
clinical significance of this interaction is not clear.
The concomitant administration of digoxin and ra-
cemic albuterol resulted in a mean decrease of 16-


PharmaNote


22% in serum digoxin levels in healthy volunteers.
The clinical significance is unclear, but it is prudent
to carefully evaluate serum digoxin levels in pa-
tients receiving levalbuterol. Levalbuterol should
be administered with extreme caution to patients
who are using monoamine oxidase inhibitors
(MAOIs) or tricyclic antidepressants (TCAs), or
within two weeks of discontinuing such agents.

Cost
The average cost of levalbuterol for inhala-
tion 0.63 mg/3 ml and 1.25 mg/3 ml is $2.27 per
unit or approximately $204 per month if dosed
three times daily.21 This is based upon a survey of
national community pharmacy prices. Price com-
parison can be difficult due to differences in dosage
and packaging, but the price of levalbuterol is ap-
proximately 3-4-fold greater than racemic albuterol.
Table 7 depicts a summary of retail prices from
several pharmacies located in Gainesville, FL. In
general, the average price per unit (3 ml vial) of
albuterol is $0.94 while levalbuterol 1.25 mg is
$3.16 and levalbuterol 0.63 mg is $3.22.

Summary
Asthma is a major health problem in the
United States, affecting millions of people and re-
sulting in significant morbidity and mortality and a
reduced quality of life. Levalbuterol is one of the


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FI







Table 6. Mean change from baseline in heart rate (15 min.) and glucose and potassium (60 min.) in patients >12 years.4'14
Mean Changes (day 1)
Potassium (mEq/
Heart rate (bpm) Glucose (mg/dL) L)
Levalbuterol 0.63 mg (n=72) 2.4 4.6 -0.2
Levalbuterol 1.25 mg (n=73) 6.9 10.3 -0.3
Racemic albuterol 2.5 mg (n=74) 5.7 8.2 -0.3
Placebo (n=75) -2.8 -0.2 -0.2


first of a new trend in pharmaceutics where a spe-
cific isomer has been isolated and marketed. The
motivation for developing certain enantiomers has
been the desire to improve efficacy and reduce ad-
verse effects. The (S)-isomer is responsible for air-
way hyperreactivity and decreased efficacy of race-
mic albuterol if administered on a regular basis.
While several studies have demonstrated the thera-
peutic bronchodilating action is the result of the
(R)-isomer, the improved efficacy and possible ad-
vantages over racemic albuterol is subject to debate
due to study design and conflicting results. The (S)-
isomer may also be responsible for adverse effects
associated with racemic albuterol, but the data
again has proven conflicting on this matter. In the
United States, the price of levalbuterol is several
times more expensive than generic racemic al-
buterol. There is a lack of studies proving that the
increased drug costs associated with levalbuterol
use is offset by decreased downstream medical
costs associated with hospitalization, etc. Until this
question is settled, there will always be debate as to
whether or not its use is justified as first line ther-
apy or if it should be reserved as an alternative for
those who suffer adverse effects with racemic al-
buterol.

References
1. NHBLI, National Asthma Education and Pre-
vention Program, Expert Panel Report 2.
Guidelines for the diagnosis and management
of asthma. NIH Publication No. 97-4051. Be-
thesda, MD, U.S. Department of Health and
Human Services, 1997.
2. Mannino DM, Homa DM, Akinbami LJ,
Moorman JE, Gwynn C, Redd SC. Surveil-
lance for asthma United States, 1980-1999.
MMWR Surveillance Summaries 2002;51
(SS01):1-13.


3. Williams SG, Schmidt DK, Redd SC, Storms
W. Key clinical activities for quality asthma
care: recommendations of the National Asthma
Education and Prevention Program. MMWR
Recomm Rep 2003;52:1-8.
4. Xopenex(levalbuterol) Package Insert. Marl-
borough, MA: Sepracor Inc., 2002.
5. Gumbhir-Shah K, Kellerman DJ, Koch F, Jusko
WJ. Pharmacokinetics and pharmacodynamics
of cumulative single doses of inhaled salbuta-
mol enantiomers in asthmatic subjects. Pulm
Pharmcol Ther 1999;12:353-62.
6. Milgrom H, Skoner D, Bensch G, et al. Low-
dose levalbuterol in children with asthma:
Safety and efficacy in comparison with placebo
and racemic albuterol. J Allergy Clin Immunol
2001;108:938-945.
7. Clinical Pharmacology Online. Available at
http://cp.gsm.com. Accessed February 9, 2005.
8. Penn RB, Frielle T, McCullough JR, Aberg G,
Benovic JL. Comparison of R-, S-, and RS-
albuterol interaction with human beta 1- and
beta 2-adrenergic receptors. Clin Rev Allergy
Immunol 1996;14:37-45.
9. Mitra S, Ugar M, Ugar O, Goodman M,
McCullough JR, Yamaguchi H. (S)-albuterol
increases intracellular free calcium by mus-
carinic receptor activation and a phospholipase
C-dependent mechanism in airway smooth
muscle. Mol Pharmacol 1998;53:347-354.
10. Agrawal DK, Ariyarathna K, Kelbe PW. (S)-
albuterol activates pro-constrictory and pro-
inflammatory pathways in human bronchial
muscle cells. J Allergy Clin Immunol
2004;113:503-510.
11. Volcheck GW, Gleich GJ, Kita H. Pro- and
anti-inflammatory effects of beta adrenergic
agonists on eosinophil response to IL-5. J Al-
lergy Clin Immunol 1998;101:S35.


Phrm~oe olme20 Isu 8 My 00


Volume 20, Issue 8, May 2005


PharmaNote







Table 7. Phone survey of drugs costs in selected Gainesville area pharmacies
Drug Dose Pharmacy #1 Pharmacy #2 Pharmacy #3 Pharmacy #4 Average
Albuterol 2.5 mg/3 ml $25.99/25 vials $26.09/25 vials $27.99/25 vials $13.84/25 vials $23.48
Levalbuterol 1.35 mg/3 ml $70.99/24 vials $80.99/24 vials $77.95/24 vials $73.34/24 vials $75.82
Levalbuterol 0.63 mg/3 ml $75.99/24 vials $80.99/24 vials $78.95/24 vials $73.34/24 vials $77.32


12. Templeton AGB, Chapman ID, Chilvers E,
Morley J, Handley DA. Effects of (S)-albuterol
on isolated human bronchus. Pulm Pharmacol
1998;11:1-6.
13. Lipworth BJ, Clark DJ, Koch P, Arbeeny C.
Pharmacokinetics and extrapulmonary 32 adre-
noreceptor activity of nebulised racemic salbu-
tamol and its R and S isomers in healthy volun-
teers. Thorax 1997;52:849-852.
14. Nelson HS, Bensch G, Pleskow WW, DiSan-
tostefano R, DeGraw S, Reasner DS, et al. Im-
proved bronchodilation with levalbuterol com-
pared with racemic albuterol in patients with
asthma. J Allergy Clin Immunol 1998;102:943-
52.
15. Chowdhury BA. J Allergy Clin Immunol
2002;110:324; author reply 325-8.
16. Asmus MJ, Hendeles L, Weinberger M, et al. J
Allergy Clin Immunol 2002;110:325; author
reply 325-8.
17. Ramsay CM, Cowan J, Flannery E, McLachlan
C, Taylor DR. Bronchoprotective and bron-
chodilator effects of single doses of (S)-
salbutamol, (R)-salbutamol and racemic salbu-
tamol in patients with bronchial asthma. Eur J
Clin Pharmacol 1999;55:353-9.
18. Lotvall J, Palmqvist M, Arvidsson P, Maloney
A, Ventresca GP, Ward J. The therapeutic ratio
for R-albuterol is comparable with that of RS-
albuterol in asthmatic patients. J Allergy Clin
Immunol 2001;108:726-31.
19. Truitt T, Witko J, Halpem M. Levalbuterol
compared to racemic albuterol: Efficacy and
outcomes in patients hospitalized with COPD
or asthma. Chest 2003;123:128-153.
20. J, Myers TR, Kirchner L, Kercsmar CM. Com-
parison of racemic albuterol and levalbuterol
for the treatment of acute asthma. J Pediatr
2003;143:731-6.
21. Pillbot.com. Available at http://
www.pillbot.com. Accessed February 9, 2005.


Ibandronate (BonivaTM), an oral
bisphosphonate, has been approved as a once
monthly option for the prevention and
treatment of postmenopausal osteoporosis. It
is the first oral drug for a chronic disease
approved in a once monthly dosage form.
Boniva had previously been approved for
once daily use but was never marketed in the
United States. The dose is 150 mg on the
same day once each month for both
prevention or treatment. If a dose is missed,
patients can be counseled to take BonivaTM
on the first morning they remember,
provided the next dose is not scheduled
within the next 7 days. The previous dosing
schedule should then be resumed. BonivaTM
should be taken on an empty stomach with 6-
8 ounces of water immediately upon waking
and patients must remain upright for at least
1 hour.




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

Benjamin J. Epstein Assistant Editor
Pharm.D.


m:m
PharmaNote Volume 20, Issue 8, May 2005


Volume 20, Issue 8, May 2005


PharmaNote




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