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APIDRA: A RAPID-ACTING
INSULIN FOR THE TREATMENT
OF DIABETES

Jessica Ball, Pharm.D. Candidate


Current estimates report that more than 18 mil-
lion Americans have diabetes (approximately 6.3%
of the population). Of these, 13 million are diag-
nosed, while 5.2 million are unaware of their dis-
ease.1 Among adults diagnosed with diabetes in
2002, about 12% require insulin and oral medica-
tions, 19% administer insulin alone, 53% take oral
medications, and 15% are untreated.1 Diabetic pa-
tients with uncontrolled hyperglycemia are at
greater risk for diabetes-related complications and
premature death. In 2000, diabetes was the 6th lead-
ing cause of death according to a conservative esti-
mate. Furthermore, diabetes is the leading cause of
ESRD, adult blindness, non-traumatic lower-
extremity amputation, and impotence. Heart disease
and stroke are 2 to 4 times more likely in a patient
with diabetes. In 2002, diabetes-related complica-
tions (amputation, death from cardiovascular dis-
ease or stroke, and nervous system disease) oc-
curred in 60-70% of diabetic patients.l Diabetes
costs the United States $132 billion per year in
2002, with direct medical costs accounting for $92
billion while indirect costs (disability, work loss,
premature mortality) consume an additional $40
billion.1


Insulin replacement is the bedrock for manage-
ment of type 1 DM and is often necessary to con-
trol diabetes and prevent complications in type 2
patients with more advanced disease. Reduced
blood glucose is directly related to improved out-
comes. It is estimated that for every 1% decrease in
the hemoglobin Alc (HbAlc) the risk of microvas-
cular complications (eye, kidney and nerve disease)
is reduced by 40%.1 Early administration of insulin
is associated with P-cell preservation. Furthermore,
insulin receptor substrate (IRS)-2 has been impli-
cated in 3-cell growth and survival.2 Regular insu-
lin inhibits P-cell apoptosis by 15%, while insulin
glulisine (Apidra), a new rapid-acting insulin and
IRS-2 substrate, provides a 55-60% inhibition of
apoptosis.2 The clinical significance of this bio-
chemical effect has yet to be determined by ran-
domized clinical trials. Insuline glulisine (IG) was
approved by the FDA in April 2004. It is manufac-
tured and distributed by Aventis Pharmaceuticals
under the trade name Apidra. IG is indicated for
the treatment of adult patients with diabetes melli-
tus. This article will explore evidence-based trials
to delineate the safe and effective use of IG.




INSIDE THIS ISSUE:
APIDRA: A RAPID-ACTING INSULIN FOR THE
TREATMENT OF DIABETES
SANCTURA: A NEW ALTERNATIVE FOR
OVERACTIVE BLADDER


mm
PharmaNote Volume 20, Issue 5, February 2005


PharmaNote


VOLUME 20, ISSUE 5 FEBRUARY 2005


PharmaNote


Volume 20, Issue 5, February 2005








Table 1. Pharmacokinetics of insulin glulisine compared to insulin aspart
Following subcutaneous injection


Kinetic Parameters
Bioavailablity
Cmaxt


Glulisine


-70%
82 mU/L
55 minutes


Tmax


413 Liters


Route of elimination
Half-life
Onset of action
Duration of action


Dual


42 minutes


10-15 minutes
3.5-5 hours


Data compiled from reference 3. *Vd after IV administration. tCmax is dose-dependent; data reflects Cmax following 0.15 U/kg subcutaneous injection :A
small portion is inactivated by peripheral tissues, but the majority is metabolized by the liver and kidneys. Insulin is filtered and reabsorbed by the kidneys.
Abbreviations: Cmax maximum concentration reached after administration; Tmax-time from administration to Cmax; Vd volume of distribution; U units;
kg kilograms; mU micro units; mL milliliter.


Pharmacology and Pharmacokinetics
The pharmacology of IG is similar to other
insulins except it is more selective for IRS-2 in
pancreatic p-cells compared to aspart (Novolog),
lispro (Humulog), and regular insulins.2 In vitro,
this selectivity is responsible for enhanced P-cell
protection against cytokine- and fatty acid-
mediated apoptosis.2 However, the clinical signifi-
cance of this selectivity in vivo can only be deter-
mined by reliable clinical trials. The pharma-
cokinetics of IG are comparable to other rapid-
acting insulins and are summarized in Table 1.

Clinical Trials
The safety and efficacy of IG has been
evaluated in type 1 and 2 diabetic patients. The pri-
mary outcome in these studies was glucose control
measured by HbAlc. These studies compared IG
versus lispro (Humalog), aspart (NovoLog) and
regular insulin. Insulin glargine(Lantus") or NPH
where concomitantly administered as basal insulin
in each case. (Table 2)

Type I Diabetes
There are three phase III trials conducted in
type I diabetic patients. One of these studies was
designed to determine the safety and efficacy of IG
compared to lispro (IL). Another study was de-
signed to determine the safety and efficacy of IG
administration before and after a meal compared to
regular insulin. The final study was designed to de-


mharmaNote


termine the compatibility of IG administered via a
pump compared to insulin aspart.
In a 26 week, randomized, open-label, active-
control study Dreyer and colleagues evaluated the
safety and efficacy of IG compared to I.3'4 (Table
2) This study was designed to show noninferiority
of IG compared to IL with respect to glycemic con-
trol. The study included 672 type 1 diabetic pa-
tients. The baseline demographics between treat-
ment groups were comparable except for history of
diabetes, and duration of insulin treatment, which
were approximately 2 years longer in the IG group.
A 4-week run-in phase with insulin glargine and
lispro provided uniform dosing for optimal 2-hour
postprandial and fasting blood glucose. IG and IL
were administered 0-15 minutes before each meal.
Glargine was administered as the basal insulin at
bedtime. Glycemic control measured by reductions
in HbAlc (-0.14% from 7.6% for both groups) and
rates of hypoglycemia were comparable for both
treatment groups. However, during the study, pa-
tients in the IG group required significantly less up-
ward titration of basal insulin (compared to base-
line, the increase was 0.12 IU for IG vs. 1.82 IU for
IL; p=0.0001). There was also a statistically signifi-
cant difference in the total insulin dose (compared
to baseline, -0.86 IU for IG vs. +1.01 IU for IL;
p=0.0123). Thus, the IG group experienced a simi-
lar decrease in HbAlc with less total insulin com-
pared to the IL group. More cardiac and muscu-
loskeletal events were seen in the IG group com-


Volume 20, Issue 5, February 2005


Asnart


-70%


82 mU/L


40-50 minutes


Dual


81 minutes
5-15 minutes
3.5-5 hours


F


Asnart


harma"ote












Randomized, parallel,
open-label, active-control

672


Study 3006*
Type I Diabetes


Study 3004*


Pivotal Study* 3002
Type II Diabetes


Randomized, active- Randomized, open-label, Randomized, open-label,
control active-control active-control


97% Caucasian
58% male
Mean age=38.5 yr


< 18 y.o.
Insulin therapy
for


Lispro
Lantus

IG or ILSC 0-15min
AC; Glargine QHS

26 weeks
No difference between
groups (mild, mod or se-
vere)


Change in HbAlc (%) Both groups decreased
fromChange in HbAlc (%)0.14
from baseline by 0.14%


100% Caucasian
Mean age=45.8 yr


<18 y.o.
Insulin therapy
for < 1 yr
<6 months of CSII use
<3 months of the same
pump

Aspart
N/A

Both administered via
CSII pump

12 weeks
Comparable between
groups (requiring inter-
vention)


Similar endpoint HbAlc
6.98% vs. 7.18% for IG
vs. aspart respectively


94% Caucasian
Mean age=40.3 yr


<18 y.o.
Insulin therapy
for <1 yr



Regular
Lantus
IG 0-15 min AC or im-
mediately PC; regular
30-45 min AC; Glargine
QHS
12 weeks
Comparable between
groups (requiring inter-
vention)


Similar; IG pc vs. IG ac
0.15 (only significance
difference)


85% Caucasian
Mean age=58.3 yr
50% on oral medications

HbAlc <6%, >11.0%
Active retinopathy
Impaired hepatic and/or
renal function, cardiovas-
cular, neurologic, endo-
crine, active cancer, or
other major systemic dis-
eases
Regular
NPH

IG 0-15min AC; Regular
30-45 min AC; NPH bid

26 weeks
No difference between
groups (requiring inter-
vention)


Similar, slightly favoring
IG: -0.46 vs -0.30 for
IG and regular respec-
tively


Abbreviations: n=sample size; yr=year(s); <=less than; y/o= years) old; >=greater than; CSII=continuous subcutaneous insulin injection; IG=insulin glulisine;
IL=insulin lispro; sub-Q=subcutaneous; min=minute(s); ac=before meals; q= every; hs=at bedtime; bid-twice daily; pc=after meals; b/w=between;
mod=moderate; A HbAlc= change in hemoglobin Ale. *Study designs were multinational and multicenter as reported by the manufacturer


pared to the IL group. However, investigators de-
termined that these adverse events were not related
to IG. One explanation is that patients in the IG
group tended to be at higher cardiovascular risk
and had a longer duration of diabetes and insulin
therapy compared to the IG group.
A 12 week, randomized, open-label, active-
control study by Garg and colleagues evaluated the
safety and efficacy of IG given 15 minutes before a
meal or immediately after a meal compared to regu-
lar insulin given 30-45 minutes before a meal.3'4
(Table 2) Glargine was given to all three groups
once at bedtime as basal insulin. This study was de-


rharmaNote 40


signed to show non-inferiority of post-meal IG
when compared to pre-meal IG and pre-meal regu-
lar insulin. The study included 860 type I diabetic
patients. The baseline demographics were compara-
ble. A 4- week run-in phase with glargine and regu-
lar insulin provided uniform dosing for optimal 2-
hr postprandial and fasting blood glucose. Glyce-
mic control, measured as reductions in HbAlc
(-0.11% with post-meal IG vs. -0.26% with pre-
meal IG vs. -0.13% with regular insulin), and rates
of hypoglycemia were comparable for the 3 treat-
ment groups. The only statistically significant dif-
ference for decreased HbAlc was between post-



Volume 20, Issue 5, February 2005


Table 2. Summary of clinical trials 3'4
Clinical Trial Pivotal Study* 3001


Design


Sample Size


Patient population


Exclusion


Insulin comparator
Insulin combination


Methods

Duration


Hypoglycemia


F


"~""~"-`-







Table 3. Important considerations for insulin glulisine 3'4
Kinetics will vary with individuals, site of injection, blood
supply, temperature and physical activity
May not provide adequate glycemic control when used as
monotherapy
Hypoglycemia similar to other insulins
Renal impairment may require reduced dosing
Should not be diluted or mixed with other insulins
Other considerations parallel those of other insulins


and pre-meal IG, favoring pre-meal administration
(p=0.0062). Adverse drug reactions were similar
between the groups with the exception of weight
gain, which was greater with pre-meal dosing of IG
and regular insulin.
A 12 week, randomized, active-control study by
Hanaire-Broutin and colleagues was designed to
evaluate the compatibility and safety of IG admini-
stration via continuous subcutaneous insulin infu-
sion (CSII) compared to insulin aspart administered
via CSII.3'4 Both insulins were bolused immediately
before meals with a continuous basal rate. The
study included 59 Caucasian type I diabetic pa-
tients. The baseline demographics were compara-
ble. Patients underwent a 4-week run-in phase with
insulin aspart. The 2 pumps used were the Dise-
tronic pump H-Tron plus V100 (66.1%) and the
MiniMed programmable pump (30.5%). Glycemic
control measured by HbAlc (increased 0.21% with
IG vs 0.10% with aspart) and rates of hypoglyce-
mia or hyperglycemia were comparable for both
treatment groups. Adverse reactions, such as num-
ber of catheter occlusions per month (0.08 with IG
vs 0.15 with aspart), infusion site reactions (10.3%
with IG vs 13.3% with aspart), and treatment emer-
gent adverse events(10.3% with IG vs 13.3% with
aspart) were also similar between the groups.

Type II Diabetes
In a 26 week, randomized, open-label, active-
control study, Dailey and colleagues evaluated the
safety and efficacy of IG given 15 minutes before a
meal compared to regular insulin administered 30-
45 minutes before a meal in 876 patients.5 NPH
was given twice daily as basal insulin in both
groups. Most patients mixed the short-acting insu-
lin with NPH prior to injection (74% IG vs. 83%
regular). Patients were continued on oral medica-
tions. The study was designed to demonstrate non-
inferiority of IG compared to regular insulin. The
baseline demographics were comparable, except


rharmaNote


age and duration of diabetes (IG group was older
and had diabetes for approximately 1.3 years
longer). A 4-week run-in period with NPH and
regular insulin was included in the protocol. Reduc-
tions in HbAlc were greater for the IG group (-
0.46% IG vs. -0.30% regular insulin; p<0.05) prov-
ing non-inferiority of IG. This statistically signifi-
cant difference between both groups was main-
tained through week 26 in an extension phase of the
trial.3'4 Adverse reactions, including severe hypo-
glycemia, were comparable for both treatment
groups.5 In the long-term extension study, there
was no statistically significant difference in adverse
reactions between the groups.3'4

Dosing/Administration
Dosing and administration of IG are similar
to other insulins, most closely resembling rapid-
acting insulin.3'4 IG dosing should be individual-
ized. Routes of administration supported by clinical
trials include subcutaneous injections and CSII. In-
jection sites include the abdomen, deltoid, and
thigh. As with other insulins, patients should rotate
around a site of injection. IG should be adminis-
tered 15 minutes before to 20 minutes after a meal
via subcutaneous injection. The onset of action
(rate of absorption) may be affected by injection
site, exercise, and other variables. IG should not be
mixed with other insulins or diluents. Important
consideration are listed in Table 3.

Cost/How Supplied
Apidra is not yet available for sale to the pub-
lic and therefore pricing is not yet established. It
will be reportedly launched to the market early in
2005 in a pre-filled pen device (Personal communi-
cation with Aventis, Octoberl5, 2004). Apidra U-
100 is a clear, aqueous and colorless solution sup-
plied in a 10 mL vial.

Toxicity and Safety
The safety and toxicity profiles are similar to
other rapid-acting insulins. (Table 4) The most
common adverse reaction is hypoglycemia (Table
4). Adverse reactions occurring in 5% or more of
patients include: upper respiratory tract infection,
peripheral edema, arthralgia, nasopharyngitis, diar-
rhea, influenza, headache, back pain, UTI, bronchi-
tis and sinusitis.



Volume 20, Issue 5, February 2005


F


harma"ote








Table 4. Adverse Events Documented During Clinical Trials 3'4
IGa ILa IGb Regularb IGe Regular' IGd Aspartd
Adverse Event
(n=672) (n=672) (n=876) (n=876) (n=860) (n=860) (n=59) (n=860)
Severe hypoglycemia 7.0% 3.5% 3.9% 2.7% 8.4%* 10.1%

1st time hypoglycemia 3.0% 3.1% -

Similar to Similar to Similar to Similar to
Weight changes baseline baseline +1.8 kg +2.0 kg +/-3 kg** +3 kg baseline baseline
baseline baseline baseline baseline
Catheter occlusions/mo 0.08 0.15
10.3% 13.3%
Injection site reactions 3.2% 2.3% 1(3o) (30
(3/29) (4/30)
a Study 3001 as reported by manufacturer; b Study 3002 as reported by manufacturer; c Study 3004 as reported by manufacturer; d Study 3006 as reported by
manufacturer; *For both pre- and post-meal IG; **Pre-meal IG increased by 3 kg vs. post-meal IG decreased 3 kg.


Summary
Insulin glulisine (IG) is a novel, rapid-
acting insulin that has selectivity for the IRS-2 re-
ceptor. The importance of this receptor selectivity
is currently being elucidated. In vitro, IRS-2 selec-
tivity appears to be beta-cell protective and might
delay the progression of diabetes or permit utiliza-
tion of lower total insulin doses. However, the
clinical significance of this selectivity in vivo has
not been proven in a long-term trial. IG is indicated
for both type I and II diabetes and appears to be
comparable to other rapid acting insulins, such as
insulin lispro. Until additional research on the
long-term use of IG establishes a clear advantage
over other insulins, it's role in the management of
diabetes will be comparable to that of the already
widely used rapid-acting insulins.

References

1. American Diabetes Association. National diabetes fact
sheet. Available at www.diabetes.org/diabetes-statistics/
national-diabetes-fact-sheet.jsp. Accessed October 15,
2004.
2. Rakatzi I, Speipke G, and Eckel J. [LysBe, GluB29] insu-
lin: a novel insulin analog with enhanced B-cell protective
action. Biochemical and Biophysical Research Communi-
cations 2003;310:852-859.
3. Package Insert. Aventis Pharmaceuticals. Available at
www.aventis-us.com/PIs/apidra. Accessed September 30,
2004.
4. Data on file with Aventis Pharmaceuticals.
5. Dailey G, Rosenstock J, Moses R, et al. Insulin glulisine
provides improved glycemic control in patients with type
2 diabetes. Diabetes Care 2004;27:2363-2368.




PharmaNote 0r


SANCTURA: A NEW
ALTERNATIVE FOR
OVERACTIVE BLADDER

Emerson Molina, Pharm.D. Candidate


Approximately 15-30% of elderly persons liv-
ing at home, one third of those in the acute-care set-
ting, and at least half of those in nursing homes suf-
fer from urge incontinence. The condition increases
with increasing age and affects twice as many
women as it does men.1 Urge incontinence is a con-
dition where urinary storage is inadequate because
of over-activity of the detrusor muscle. The most
common symptoms include urinary incontinence,
urgency, and frequency. The term frequency is de-
fined as emptying the bladder more than 8 times
daily. Symptoms can be disturbing since nocturia
and enuresis are also common. It is important that
patients receive adequate treatment because un-
treated or under-treated, it can lead to social isola-
tion, low quality of life, low self-esteem, and can
affect general health.1
The etiology of urinary incontinence is often
unknown but often referred to as idiopathic detru-
sor instability. Nonpharmacological treatments
such as limiting intake of caffeine and alcohol and
decreasing evening fluid consumption can help
minimize the symptoms of urge incontinence.1 Pel-


Volume 20, Issue 5, February 2005


F


"~""~"-`-








Table 1- Urodynamic Parameters8
Increase in maximum Increase in volume at first Increase in volume at first
Medication Difference bladder capacity (ml) unstable contraction (ml) sensation to void (ml)
92.0 63.5 73.6
Start to Week 26
N=203 N=63 N=201
Trospium
Trosm 115.0 46.1 78.6
Start to Week 52
N=189 N=51 N=186
117.0 61.2 76.93
Start to Week 26
N=65 N=20 N=64
Oxybutynin
119.4 36.7 70.2
Start to Week 52 N1862
N=62 N=18 N=62


vic floor muscle rehabilitation, acupuncture, and
scheduling regimens such as timed voiding, habit
retraining, and bladder training may also help with
urge incontinence, but are cumbersome in clinical
practice.
Treatment options for patients include anticho-
linergic medications such as oxybutynin
(Ditropan) and hyoscyamine sulfate (Levsin).
Anticholinergic agents work by antagonizing mus-
carinic cholinergic receptors, blocking efferent
parasympathetic nerve impulses, which induce de-
trusor contraction. These drugs are associated with
a high incidence of adverse effects because of the
widespread activity of the parasympathetic nervous
system. These drugs also increase bladder volume
and should not be used in patients with urinary re-
tention. Currently, tolterodine (Detrol), a com-
petitive muscarinic receptor antagonist, and oxybu-
tynin (Ditropan), a tertiary amine exerting an-
timuscarinic and antispasmodic activity on smooth
muscle, are considered first-line treatments for urge
incontinence.2 Other agents available for the treat-
ment of urinary incontinence are tricyclic antide-
pressants (TCAs) such as desipramine and nortrip-
tyline, alphai-adrenergic agonists such as prazosin,
and antispasmodic agents such as flavoxate and es-
trogen. TCAs have antimuscarinic activity that is
helpful with urinary incontinence especially noctur-
nal enuresis, but they have extensive side effects.
Antispasmodic agents such as flavoxate are less ef-
fective than oxybutynin.4 Evidence regarding the
use of estrogen is inconclusive but estrogens may
be helpful in the adjunctive treatment of postmeno-
pausal women with symptoms of urgency, fre-
quency, and nocturia. Unfortunately, the role of
hormone replacement therapy has diminished in
light of findings from the Women's Health Initia-


tive studies.9 Trospium chloride (Sanctura) manu-
factured by Odyssey Pharmaceuticals was approved
by the FDA in May 2004 for the treatment of over-
active bladder with symptoms of urge urinary in-
continence, urgency, and frequency. This article
will examine the safety, efficacy, and tolerability of
trospium.

Pharmacology and Pharmacokinetics
Trospium is an antispasmodic and non-specific
antimuscarinic agent. It antagonizes the effect of
acetylcholine on muscarinic receptors in cholinergi-
cally innervated organs, thereby reducing smooth
muscle tone in the bladder. Trospium decreases the
frequency of voluntary and involuntary detrusor
contractions and increases maximum cystometric
bladder capacity and volume at first detrusor con-
traction.5 As a result, trospium decreases urinary
urgency, frequency, and incontinence. When used
at therapeutic doses, trospium has negligible affin-
ity for nicotinic receptors.3 Furthermore, since
trospium is a quaternary amine it is less likely to
penetrate the blood brain barrier, which may result
in a milder side effect profile including less drowsi-
ness, nervousness, and dizziness compared to oxy-
butynin, a tertiary amine.3
Trospium's peak plasma concentrations (Cmax)
are reached at 5 to 6 hours following oral admini-
stration. Less than 10% of the dose is absorbed.5
Absorption is reduced by the simultaneous intake
of food, especially with a high fat content. For that
reason, it is recommended that trospium be taken at
least one hour prior to meals or on an empty stom-
ach. Forty percent of the absorbed dose is excreted
as metabolites while 60% is excreted unchanged in
the urine via active tubular secretion. Cytochrome
P450 (CYP450) is not believed to contribute sig-


~
PharmaNote Volume 20, Issue 5, February 2005


PharmaNote


Volume 20, Issue 5, February 2005







Table 2. Mean change from baseline* for urinary frequency, urge incontinence episodes, and void volume.5
Placebo Trospium
Efficacy Endpoint N=256 N=253 P-value
Urinary Frequency/24 hrs a, t
Mean baseline 12.9 12.7
Mean change from baseline (SE) -1.3 (0.2) -2.4 (0.2) <0.001
Urge Incontinence episodes/week b,t
Mean baseline 30.1 27.3
Mean change from baseline (SE) -13.9 (1.2) -15.4 (1.1) 0.012
Urinary void volume/toilet void (ml) a,
Mean baseline 156.6 155.1
Mean change from baseline (SE) 7.7 (3.1) 32.1 (3.1) <0.001

SE denotes standard error. Week 12 or last observation carried forward in ITT population. Denotes co-primary endpoint. aTreatment differences assessed by
analysis of variance for ITT:LOCF data set. b Treatment differences assessed by ranked analysis of variance for ITT:LOCF data set.
ITT = intention to treat, LOCF = last observation carried forward .


nificantly to the elimination of trospium, but
trospium does inhibit the CYP2D6 isoenzyme.3 The
majority of trospium is distributed into plasma,
where its plasma half-life is approximately 20
hours. Trospium has been shown to cross the pla-
centa.

Clinical Trials
A controlled, double-blind, multicenter
clinical trial was conducted to determine the toler-
ability and efficacy of trospium in doses of 20 mg
twice daily for long term therapy (52 weeks) in pa-
tients with urge syndrome.8 The trial was com-
prised of 358 patients with urge syndrome who
were randomized to either trospium 20 mg twice
daily or oxybutinin 5 mg twice daily for 52 weeks
of continuous treatment. Analysis of micturition
diaries demonstrated a reduction of the micturition
frequency (-3.5/d versus -4.2/d for trospium and
oxybutynin, respectively), incontinence frequency
(-1/day in both groups), and a reduction of the
number of urgencies (-3.5/d versus -3.6/d for
trospium and oxybutynin, respectively). Mean
maximum cystometric bladder capacity increased
during treatment with trospium by 92 mL after 26
weeks and 115 mL after 52 weeks (P=0.001).
(Table 1) Adverse events occurred in 64.8% of the
patients treated with trospium chloride and 76.6%
of those patients treated with oxybutynin. Trospium
demonstrated comparable efficacy and a better
benefit to risk ratio compared to oxybutynin due to


improved tolerability. The incidence of side effects
during 52 weeks of therapy was no greater than
during short-term therapy. Adverse events, espe-
cially xerostemia, were more frequent and began
earlier in the oxybutynin group compared with the
trospium group.
A randomized, double-blind, placebo-
controlled, parallel group study of 523 patients was
conducted to evaluate trospium for the treatment of
patients with overactive-bladder. Of the 523 pa-
tients, 262 patients received trospium 20 mg twice
daily and 261 patients received placebo. The pa-
tients were mainly Caucasian (85%) and female
(74%), with a mean age of 61 years (range 21 to 90
years.) Inclusion criteria for the trial included
symptoms of urge or mixed incontinence confirmed
by medical history and urinary diary, at least 7 epi-
sodes of urge incontinence episodes per week, and
greater than 70 micturitions per week. The symp-
tom burden at baseline is listed in Table 2. After 12
weeks, the mean change from baseline for urinary
frequency per 24 hours was -2.4 with trospium
and -1.3 with placebo. The urge incontinence epi-
sodes decreased by 15.4/wk with trospium and
13.9/wk with placebo. Urinary void volume in-
creased by 32.1 mL with trospium and 7.7 mL with
placebo.

Indications and Dosing
Trospium is indicated for the treatment of
overactive bladder with symptoms of urge inconti-


Phrm~oe olme20 Isu 5 Fbrar 20


PharmaNote


Volume 20, Issue 5, February 2005








Table 3. Most frequent adverse reactions with trospium and other overactive bladder medications.


Adverse Reaction
Dry Mouth

Constipation

Flatulence

Headache

Abdominal Pain

Fatigue
Urinary Retention
Dry Eyes
Dizziness


Trospium


20.1%

9.6%

n/a

4.2%

n/a

n/a
1.2%
1.2%

n/a


Tolterodine
39.5%
(LA, 23%)
7%
(LA, 6%)

n/a

7%
(LA, 6%)
5%
(LA., 4%)
n/a


Postural Hypotension n/a n/a n/a

LA denotes long-acting dosage form (Detrol LA)


nence, urgency, and urinary frequency. The recom-
mended dose for trospium is 20 mg twice daily on
an empty stomach at least 1 hour prior to meals.
The need for continued treatment should be as-
sessed at regular intervals of 3 to 6 months.4 For the
population older than 75 years of age, a dose of 20
mg once daily based upon tolerability should be
given. Also, a dose of 20 mg once a day at bedtime
should be administered to those patients with se-
vere renal impairment (CrCl <30 ml/min).

Precaution and Warnings/Contraindications
Age does not significantly affect the pharma-
cokinetics of trospium but it does correlate with in-
creased anticholinergic side effects; patients older
than 75 years of age are more likely to experience
anticholinergic symptoms (e.g., xerostomia, consti-
pation, cognitive impairment). Trospium is contra-
indicated in patients with urinary retention, gastric
retention, or uncontrolled narrow-angle glaucoma
and in patients who are at risk for these conditions.
Precautions should be observed in patients with re-
nal insufficiency and hepatic impairment. In pa-
tients with severe renal insufficiency (CrCl <30 ml/
min), dose modification is recommended. A dose of
20 mg once a day at bedtime should be adminis-
tered to this population. In patients with mild or
moderate hepatic impairment, Cmax increases by


12% and 63%, respectively; however, the mean
AUC is unchanged.3 The effect of severe hepatic
impairment on the pharmacokinetics of trospium is
unknown; therefore, caution is advised in this
population.

Adverse Reactions
The two most common adverse events ex-
perienced by patients receiving trospium 40 mg/d
are dry mouth and constipation. The severity of
xerostemia seems to be less severe than that en-
countered by patients on oxybutynin.6 Also, since
trospium does not readily cross the blood brain bar-
rier or conjuctiva, anti-muscarinic-related adverse
events such as xerophthalmia, blurred vision, and
other CNS-related events might occur less fre-
quently.3 Table 3 lists the frequency of common ad-
verse effects compared to other agents used for
overactive-bladder.
As with all anticholinergics, major effects of
overdosage include delirium, hallucinations, tachy-
cardia, hypertension, hypotension, altered mental
status, mydriasis, peripheral vasodilation, coma,
seizures, and diminished bowel signs.4 Effects may
be delayed and cyclical. Symptomatic and suppor-
tive treatments should be provided in such in-
stances. Rarely, life-threatening dysrhythmias
(including bradycardia), cardiogenic shock, or car-


PhamaoteVoum 20 Isue5,Feruay 00


Oxybutynin
61-71%

13%


n/a

n/a

2-7%


6-16%


PharmaNote


Volume 20, Issue 5, February 2005







Table 4. Cost of Common Overactive Bladder Treatments

Drug Regimen Cost
Trospium 20 mg twice daily $91.49
Tolterodine 2 mg twice daily $117.79
Tolterodine LA 4 mg daily $101.89
Oxybutynin 5 mg twice daily $18.99
Oxybutynin XL 5 mg daily $100.99
Flavoxate 100 mg three times daily $54.79

Cost calculated based on the average retail cost of one-month supply from 3 local pharmacies, Gainesville, FL.


diorespiratory arrest have been reported with anti-
cholinergic drugs.4 Therefore, ECG monitoring is
recommended in the event of overdosage since
tachycardia and ventricular arrythmias could occur.
It is not known whether or not trospium is excreted
into breast milk; caution is advised when trospium
is administered to a woman who is breast-feeding
due to potential newborn exposure and decreased
milk volume.

Drug Interactions
Currently, there are no in vivo drug-drug in-
teraction studies available to assess the pharma-
cokinetic effects of concomitant medications taken
with trospium. In vitro studies suggest that no clini-
cally relevant interactions are expected. However,
drugs that are actively secreted may interact with
trospium by competing for renal tubular secretion,
resulting in an increase in the serum concentration
of trospium and/or the coadministered drug. Also,
co-administration of trospium with medications that
exhibit anticholinergic effects can cause additive
anticholinergic effects. Furthermore, trospium, like
other antimuscarinic drugs, can raise gastric pH re-
ducing the oral bioavailability of medications that
require an acidic environment for absorption (eg.
ketoconazole).7 Trospium is an inhibitor of
CYP2D6; however, drug interactions via cyto-
chrome P-450 pathways have not proven to be sig-
nificant in in vitro models. This is because at the
usual oral regimen of trospium, serum concentra-
tions do not reach sufficient concentrations to in-
hibit CYP2D6.

Cost
Comparative cost data for medications used
to treat overactive bladder are presented in Table 4.


Summary
Trospium chloride is a new antimuscarinic
agent that has been used in Europe for over 20
years. It has recently been approved by the FDA for
the treatment of overactive bladder with symptoms
of urge incontinence, urgency, and urinary fre-
quency. Trospium may be better tolerated than cur-
rently available anticholinergic agents. Trospium
adds to the limited arsenal of medications available
to treat overactive bladder and may offer sympto-
matic relief to patients unable to tolerate older
agents.

References
1. Imam, Khaled. The Role of the Primary Care Physician in
the Management of Bladder Dysfunction. Reviews in
Urology 2004;6(suppl 1):S38-S44
2. Dipiro JT et al. Pharmacotherapy: A pathophysiological
Approach, 5th ed.; Appleton and Lange; 2002.
3. Clinical Pharmacology, Gold Standard Multimedia 2004:
http://cpip.gsm.com
4. Gelman CR, Rumack BH, Hutchinson TA: Drugdex Sys-
tem. MICROMEDEX, Inc., Englewood (CO): (Edition
expires 2004)
5. Sanctura [Package Insert]. Lexington, MA; Indevus
Pharmaceuticals; 2004.
6. Madersbacher H, Stohrer M, Richter R, et al. Trospium
chloride versus oxybutynin: a randomized, double-blind,
multicentre trial in the treatment of detrusor hyperre-
flexia. Br J Urol 1995;75:452-6
7. Pfeiffer A, Schmidt T, Holler T, et al. Effect of trospium
chloride on gastrointestinal motility in humans. Eur J
Clin Pharmacol 1993;44:219-23.
8. Halaska M, Ralph G, et al. Controlled, double-blind,
multicentre clinical trial to investigate long-term toler-
ability and efficacy of trospium chloride in patients with
detrusor instability. World J Urol 2003;20:392-9.


4 4 4


40IU


PharmaNote


Volume 20, Issue 5, February 2005










New Drug Approvals


Eu q


* Eszopiclone (LunestaTM, Sepracor Inc.),
Sn *Ic) Pregabalin (LyricaTM capsules, Pfizer), a
is the first non-benzodiazepine sedative- Pregabali (LyrcaT capsules, Pfizer), a
hypnotic indicated for the chronic follow-up drug to Pfizer's gabapentin
treatment of insomnia in patients with (Neurontin) has been approved for the
treatment of neuropathic pain associated
difficulty falling asleep or staying asleep. treatment o neuropat
The dose is 2 mg by mouth immediately with diabetic peripheral neuropathy and
before retiring. The dose can be titrated postherpetic neuralgia. Approved
to 3 mg if clinically indicated. Signs of dosages are not yet available, but the
withdrawal have been reported with effective dosage range in clinical trials
abrupt discontinuation in clinical studies appears to be 300-600 mg/day.
of 6 months and 6 weeks duration. Pregabalin is a controlled substance, but
Eszopiclone is a CYP3A4 substrate; DEA classification is pending. Common
inhibitors of this enzyme may decrease adverse reactions reported include
systemic clearance of eszopiclone dizziness, somnolence, peripheral edema,
leading to prolonged effects. blurred vision, weight gain, difficulty
with concentration/attention, and dry
* Darifenacin (Enablex extended-release mouth.
tablets, Novartis Pharmaceuticals) is a
competitive, selective M3 muscarinic
antagonist approved for the treatment of
overactive bladder and associated
symptoms. The recommended starting
dose is 7.5 mg daily. Based on initial
response, the dose may be increased to -__ __--------_-
15 mg daily as early as 2 weeks after Te P is P is
initiating therapy. For patients with The PharNote is Pubsheby
moderate hepatic impairment or when Te De r e Pa a
coadministered with a potent CYP3A4 Services, UF Family Practice Medical
inhibitor, the maximum dose is 7.5 mg. Group, Departments of Community
Health and Family Medicine and
* Solifenacin (Vesicare, Pharmacy Practice
GlaxoSmithKline), a competitive, University of Florida
selective M3 muscarinic antagonist,
improves bladder control and is
comparable to tolterodine in safety and
other efficacy parameters. The initial John G. Gums Editor
John G. Gums Editor
dose is 5 mg once daily for the treatment Pharm.D.
of overactive bladder, but may be
increased to 10 mg daily. In patients R. Whit Curry, M.D. Associate Editor
treated with CYP3A4 inhibitors, or with
significant renal or hepatic impairment Benjamin J. Epstein Assistant Editor
the maximal recommended dose is 5 mg Pharm.D.
once daily.


i


irl-


New Drug Approvals (continued)


I


~R~~~I~~~~~~~~~~~~~~~


PharmaNote


Volume 20, Issue 5, February 2005




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