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LUBIPROSTONE (AMITIZA):
THE FIRST CHLORIDE CHANNEL
ACTIVATOR FOR THE TREAT-
MENT OF CHRONIC IDIOPATHIC
CONSTIPATION

Stacie Williams, Pharm.D. Candidate



Constipation is an exceedingly common com-
plaint. Recent reports estimate that between 2% and
27% of North Americans suffer from constipation.1
For many patients, constipation is a chronic condi-
tion that lasts for months and can potentially become
severe. In 2002, 398,000 people were hospitalized
for constipation and of these 121 deaths occurred.2
There are many prescription and non-prescription
products that have been marketed for constipation.
These include the bulk-forming, osmotic, stimulant,
and lubricant laxatives and stool softeners. Some pa-
tients can achieve full relief from these products, al-
though some remain symptomatic.
The discovery of a new type of chloride channel
may be the answer for those patients who have
chronic constipation. Most of the chloride transport
in the intestinal epithelium is through the cystic fi-
brosis transmembrane conductance regulator
(CFTR), but it was found that there are also type 2
chloride channels (C1C-2) in these cells.3 Lubipros-
tone (Amitiza [a ma te' za]) is a new drug that acti-
vates C1C-2 channels in order to alleviate constipa-
tion. The manufacturer, Takeda Pharmaceuticals,
received approval by the FDA in January 2006 to
market lubiprostone for the indication of chronic
idiopathic constipation in adults.4 This article will


review lubiprostone's kinetics, safety, and efficacy
data.

Pharmacology and Pharmacokinetics
Lubiprostone, also referred to as SPI-0211 or
RU-0211, is the first of a new class of drugs called
prostones. These prostones are bicyclic fatty acids
that are derivatives of a metabolite of prostaglandin
El, though they have a negligible effect on pros-
taglandins E and F.5 Type 2 chloride channels are
located on the apical portion of gastrointestinal (GI)
epithelium. Once they are activated, chloride moves
out of these cells into the lumen of the intestinal
tract. Sodium follows chloride out of the cell in order
to retain neutrality. Once sodium leaves, water does
as well so that isotonicity is maintained.6 This leads
to an increase in intestinal fluid so that stools are sof-
tened and motility increased. Serum electrolyte con-
centrations remain unaltered.7 Lubiprostone is highly
specific for C1C-2 channels; CFTR is not activated
by this compound.8
Lubiprostone is administered orally, but due
to low systemic availability, plasma concentrations
are so low they cannot be quantified. Metabolism
occurs by oxidation and reduction via carbonyl re-



INSIDE THIS ISSUE:
LUBIPROSTONE (AMITIZA'): THE FIRST CHLORIDE
CHANNEL ACTIVATOR FOR THE TREATMENT OF
CHRONIC IDIOPATHIC CONSTIPATION

ALLI: AN OVER-THE-COUNTER ORLISTAT


am


SPharmaNote


VOLUME 22, ISSUE 12 SEPTEMBER 2007


Volume 22, Issue 12 September 2007


PharmaNote







ductase.7 The hepatic CYP450 system is not respon-
sible for its metabolism, so there is a low likelihood
of drug-drug interactions. Lubiprostone does not in-
hibit cytochrome P450 isoforms 3A4, 2D6, 1A2,
2A6, 2B6, 2C9, 2C19, or 2E1, and in-vitro studies of
human hepatocytes show no induction of the cyto-
chrome P450 isoforms 1A2, 2B6, 2C9, and 3A4.
There is one active metabolite, M3, which has a Cmax
of 41.9 pg/mL and reaches peak plasma concentra-
tion after 1.14 hours. After a single oral dose of 72
mcg radiolabeled lubiprostone, 60% of the total dose
was recovered in the urine within 24 hours and 30%
of the was recovered in the feces by 168 hours. Food
does not alter the kinetics of this drug, but it is rec-
ommended that it be taken with food to minimize
nausea. Lubiprostone has not yet been studied in pa-
tients with hepatic or renal impairment.4

Clinical Trials
There have been a few studies published that
look at the safety and efficacy of lubiprostone for
treating constipation. One preclinical study focused
on determining its effect on gastric/intestinal func-
tion and transit.5 This was a randomized, double-
blind, placebo-controlled study whose endpoints
were meal volumes tolerated, postprandial symp-
toms, as well as gastric volumes in 30 healthy sub-
jects. At 24 mcg twice a day (BID), lubiprostone
increased small bowel and colonic transit, but de-
layed gastric emptying. Fasting gastric volume was
also increased. There was no significant effect on
postprandial gastric volume or symptoms associated
with meals.
There were two Phase III clinical trials con-
ducted using lubiprostone for chronic constipation.
The first of the two was a randomized, double-blind,
placebo-controlled trial using 242 patients with

Table 1. Symptoms described in Rome II criteria10
Straining in >25% of defecations
Lumpy or hard stools in >25% of defecations
Sensation of incomplete evacuation in >25% of defecations

Sensation of anorectal obstruction/blockade in >25% of defe-
cations

Manual maneuvers (digital evacuation, support of pelvic floor)
to help progress defecation >25% of the time

Fewer than 3 defecations/week


chronic constipation.9 In this study, chronic constipa-
tion was defined as < 3 spontaneous bowel move-
ments (SBM) per week plus at least 6 months with 1
or more symptoms from Rome II criteria (Table 1).
Among the participants, 90% were females, 86%
were white, and the average age was 48.6 years.
There was a 2-week washout period before patients
were randomized to lubiprostone 24 mcg BID or pla-
cebo for 4 weeks. The patients were then followed
for 2 weeks with no drug to assess outcomes. Pa-
tients kept a diary to record bowel movements as
well as symptoms experienced during the trial. There
was a significant increase in the number of mean
weekly SBM in the lubiprostone group: 5.1 to 5.7
compared to 2.8 to 3.5 in the placebo group (p <
0.002). A significant increase in the number of bowel
movements on day one was also observed with 57%
in the lubiprostone group and 37% in the placebo
group (p < 0.003). Other improvements associated
with lubiprostone included reduced straining and im-
proved stool consistency.
A second Phase III study was a double-
blinded, multicenter, randomized, placebo-controlled
trial of 237 patients (88% of which were females).11
This consisted of a 15-day washout period then 28
days of lubiprostone 24 mcg BID or placebo. The
primary endpoint of this study was SBM frequency.
The mean weekly SBM before treatment was 1.28 in
the lubiprostone group vs. 1.52 in the placebo group.
After 28 days of treatment, the number of weekly
SBM increased with a significant difference between
groups (5.89 for lubiprostone vs. 3.99 for placebo; p
< 0.001). There was a significant amount of patients
that were classified as complete responders (defined
as >4 SBM per week without using rescue drugs) in
the lubiprostone group after week one compared to
those who received placebo (72.1% vs. 48.7%; p <
0.001). In 61.3% of patients receiving lubiprostone,
there was a SBM within 24 hours of the first dose,
compared to 31.4% in the placebo group. Table 2
summarizes the results of Phase III trials.

Dosing and Administration
Lubiprostone is currently available in 24 mcg
gelatin capsules to be given orally. It is dosed at 24
mcg BID in adults and elderly and can be reduced to
once daily if nausea is persistent. The recommended
maximum dose is 48 mcg/day. It has not been stud-
ied in children and should not be recommended in
this population. Lubiprostone can be taken with or


Phrm~oe olm 2, sse 2Setebe 20


Volume 22, Issue 12 September 2007


PharmaNote








Table 2. Comparison of lubiprostone phase III trials


Study group Design Dose Average SBM per week* SBM within first 24 hrs*



Placebo 3.1 37%
Johanson et al.9 Randomized, DB, PC
2003 N= 242 Lubiprostone 24 mcg BID 5.3 57%
(p < 0.002) (p < 0.003)



Placebo 3.99 31.4%
Johanson et al.11 Randomized, DB,
PC, multicenter
2005 N= 2 Lubiprostone 24 mcg BID 5.89 61.3%
(p <0.001) (no p value)


SBM = spontaneous bowel movement, DB = double-blinded, PC = placebo-controlled, N = number of patients
* Comparisons to placebo

without food, although nausea may be reduced if it is the most prevalent adverse effect, occurring in 31.1%
taken with meals.7 No limitations have been placed of those treated with lubiprostone compared to 5.1%
on the length of using lubiprostone. in the placebo group. With all of the clinical trials
combined, over 1100 patients received 24 mcg BID
Toxicity and Safety of lupiprostone; 3.4% reported severe nausea and
Lubiprostone is safe and tolerated fairly well 8.7% stopped treatment due to nausea. The lowest
by patients in clinical trials. The most common ad- overall incidence for nausea was seen at 24 mcg/day
verse effects are gastrointestinal events. Nausea was (17.2%) and the incidence of nausea increased with

Table 3. Percentage of adverse events in greater than 1% of patients in clinical trials4


Lubiprostone Placebo
Adverse Event 24mcg BID (N=316)
(N=1113)
%

Nausea 31.1 5.1
Vomiting 4.6 0.9
Headache 13.2 6.6
Diarrhea 13.2 0.9
Abdominal distention 7.1 2.2
Abdominal pain 6.7 2.8
Flatulence 6.1 1.9
Dizziness 4.1 1.3
Peripheral edema 3.8 0.3
Arthralgia 3.1 0.3
Dyspepsia 2.9 1.3
Chest pain 1.1 0.0
Dyspnea 2.4 0.0
Fatigue 2.3 1.9

PharmaNote Volume 22, Issue 12 September 2007







higher doses. The incidence of nausea was improved
when lubiprostone was taken with food; therefore, it
is recommended that it be taken with a meal. Diar-
rhea was another common adverse effect seen in tri-
als. Of the constipated patients that were studied,
13.2% reported diarrhea in the lubiprostone group,
compared to only 0.9% of those in the placebo
group. Treatment may need to be interrupted if diar-
rhea occurs. Other adverse reactions that occurred in
more than 1% of patients are headache, abdominal
distention, abdominal pain, flatulence, dizziness, pe-
ripheral edema, arthralgia, dyspepsia, chest pain,
dyspnea, and fatigue.4 Table 3 summarizes the ad-
verse effects reported by patients who received lubi-
prostone vs. placebo.
Lubiprostone is not recommended for use
during pregnancy (pregnancy category C).4 There
have not been any reproductive studies done in hu-
mans. In animal models12 fertility, reproduction, and
development were not affected except at doses 166
times the recommended human dose. The adverse
effects seen at these high doses were not linked di-
rectly to lubiprostone's actions, but to weight loss
that occurred while taking the drug.

Cost
The average cash price of 60 capsules of lubi-
prostone (Amitiza), or one month supply for most
adults, is $203.49 as determined by three community
pharmacies in Gainesville, FL.

Summary
Lubiprostone is a new, safe, and effective op-
tion indicated for adults with chronic idiopathic con-
stipation. It activates the C1C-2 channel in intestinal
epithelium which increases the production of intesti-
nal fluids. This produces softer stools with more mo-
tility which gives relief to patients with chronic con-
stipation. There are two Phase III trials that support
its efficacy. Many traditional laxatives do not have
sufficient data for their use.13 Lubiprostone is not
metabolized by the CYP450 system, so there is a low
likelihood of drug-drug interactions. The most com-
mon adverse effect is nausea, which improves when
taken with food. Lubiprostone's efficacy has been
proven against placebo, but studies are still needed
that compare this to other stool softeners and laxa-
tives that have traditionally been used for constipa-
tion.



PharmaNote


References
1. Harris LA. Prevalence and ramifications of
chronic constipation. Manag Care Interface 2005;
18: 23-30
2. National Digestive Diseases Information Clear-
inghouse. Digestive disease statistics: Constipa-
tion. Available at: http://digestive.niddk.nih.gov/
statistics/statistics.htm. Accessed May 15, 2007
3. Lipecka J, Bali M, Thomas A, et al. Distribution
of C1C-2 chloride channel in rat and human
epithelial tissues. Am J Physiol 2002; 282: C805-
16
4. Lubiprostone (Amitiza) [package insert]. Be-
thesda, Md: Sucampo Pharmaceuticals, Inc; 2006
5. Camilleri M, Bharucha AE, Ueno R, et al. Effect
of a selective chloride channel activator, lubi-
prostone, on gastrointestinal transit, gastric sen-
sory, and motor functions in healthy volunteers.
Am J Physiol Gastrointest Liver Physiol 2006;
290: G942-7
6. Lacy B, Levy LC. Lubiprostone: A chloride
channel activator. J Clin Gastroenterol 2007; 41:
345-51
7. Clinical Pharmacology [Amitiza]. Gold Standard
Media. Version 2.23. May 2007
8. Cuppoleti J, Malinowska DH, Tewari KP, et al.
SPI-0211 activates T84 cell chloride transport
and recombinant human C1C-2 chloride currents.
Am J Physiol Cell Physiol 2004; 287: C1173-83
9. Johanson JF, Gargano MA, Holland PC, et al.
Phase III efficacy and safety of RU-0211, a novel
chloride channel activator, for the treatment of
constipation. Gastroenterology 2003; 124: A48
10. Thompson WG, Longstreth GF, Drossman DA,
et al. Functional bowel disorders and functional
abdominal pain. Gut 1999; 45: 1143-7
11. Johanson JF, Gargano MA, Holland PC, et al.
Phase III study of lubiprostone a chloride chan-
nel-2 (C1C-2) activator for the treatment of con-
stipation: Safety and primary efficacy. Am J Gas-
troenterol 2005; 100: S328-9
12. Crawford DF, Perentesis GP, Engelke KJ, et al.
Effects of lubiprostone, a novel GI chloride acti-
vator, on reproductive and developmental toxic-
ity endpoints in rate. Am J Gastroenterol 2005;
100: A905
13. Rivkin A, Chagan L. Lubiprostone: chloride
channel activator for chronic constipation. Clini-
cal Therapeutics 2006; 28:2008-21


Volume 22, Issue 12 September 2007









ALLI: AN OVER-THE-COUNTER
ORLISTAT

Elizabeth Kent, Pharm.D. Candidate


Obesity has become a growing problem in the
United States with the incidence increasing drasti-
cally since the 1970s for both adults and children.
Roughly one third of the American population is
obese.1 An individual is classified as overweight
when they reach a body mass index (BMI) of 25 to
29.9 kg/m2 and are classified as obese when they
have a BMI of greater than or equal to 30 kg/m2. A
BMI of 30 is equivalent to being approximately 30
pounds overweight.2 People are at an increased risk
for mortality if they have obesity associated risk fac-
tors such as dyslipidemia, hypertension, coronary
heart disease, and type 2 diabetes.2
There are many treatment options for obesity,
the most common of which is a low calorie diet and
other lifestyle changes. Other options include phar-
macotherapy as well as surgery. The National Insti-
tute of Health (NIH) recommends to initially set a
more realistic goal of decreasing body weight by
10%, which can decrease the severity of obesity as-
sociated risk factors. A moderate weight loss goal of
10% is attainable and will be more easily maintained
for a longer period of time. Further weight loss may
be possible if the patient has achieved the 10% re-
duction and maintained it for at least 6 months.2
The use of pharmacotherapy for weight loss
became prevalent in the mid 1990s with the introduc-
tion of medications such as fenfluramine and dexfen-
fluramine. Pharmacotherapy was first introduced due
to the inability to maintain weight loss from diet and
physical activity alone. For approval of weight loss
medications, the FDA requires at least a 5% increase
in efficacy over placebo or a significantly higher
number of patients achieving a 5% reduction in
weight.3 Drugs such as dexfenfluramine, fenflura-
mine, sibutramine, and orlistat have been studied
most often in combination with lifestyle modifica-
tions such as a low calorie diet and exercise. Unfor-
tunately, both fenfluramine and dexfenfluramine
were withdrawn from the market due to an increased
risk of valvular heart disease and pulmonary hyper-

PharmaNote 40


tension.4
Orlistat was first introduced to the market in
1999 as a prescription only obesity medication sold
as the brand name Xenical. Orlistat was the first
drug for obesity to work non-systemically as a lipase
inhibitor. Xenical is available as a 120 mg tablet
that is to be taken with each meal that contains fat. In
2007, the FDA granted approval to GlaxoSmithKline
to market an over-the-counter (OTC) form of orlistat
sold as the brand name Alli (al' 1).5 This article will
review the safety and efficacy of the lower dose of
orlistat.

Pharmacology and Pharmacokinetics
Orlistat (tetrahydrolipstatin) is a synthetic
derivative of lipstatin, a natural product of Strepto-
myces toxytricini. It is a reversible lipase inhibitor
that works in the stomach and small intestine by
forming a covalent bond with active serine residue
site of gastric and pancreatic lipases. Normally in the
gut, gastric and pancreatic lipases hydrolyze dietary
fat in the form of triglycerides. Triglycerides are bro-
ken down to become absorbable free fatty acids
(FFA) and monoglycerides (MG). Orlistat works by
inhibiting these lipases so that the triglycerides are
not digested and the body is incapable of absorbing
FFA and MG. Orlistat has been shown to prevent the
absorption of approximately 30% of dietary fat.5
Orlistat is administered orally, but is mini-
mally systemically absorbed. Increased levels of fe-
cal fat have been seen within 24 to 48 hours. Orlistat
is greater than 99% protein bound, mainly to proteins
such as albumin and lipoproteins. Metabolism to in-
active and weakly active metabolites occurs mostly
in the gastrointestinal wall. Approximately 83% of
orlistat is excreted in the feces unchanged.6

Clinical Trials
Three clinical trials were submitted to the
Food and Drug Administration to support the safety
and efficacy of orlistat 60 mg as an over-the-counter
product.7'8'9 All three studies were randomized, dou-
ble-blind, placebo-controlled clinical trials and all
three tested the effects of orlistat in combination with
a low-energy diet.

Orlistat 120 mg vs. 60 mg in Obese Patients
Orlistat's effect on weight loss was evaluated
in a double-blind, placebo-controlled study.7 The
trial had a placebo run-in period where patients were


Volume 22, Issue 12 September 2007







Table 1. Body weight after a 4-week placebo lead-in (day 1) and over 2 years with orlistat or placebo7


Placebo


ITT
N=212


Body weight at
week 4 (kg)
Change in body
weight (kg)
Day 1
Week 24
Week 52
Week 76
Week 104


101.8 1.0


-2.73 + 0.15
-4.70 + 0.60
-4.14 + 0.56
-2.93 + 0.57
-1.65 + 0.62


I
N


Completer
N=91

101.0 + 0.8


-3.2 0.20


Orlistat 60 mg TID
TT Completer
=213 N=120


100.4 + 1.0


-2.49 0.14


-5.48 0.52 -6.92 0.64
-4.26 0.58 -7.08 0.54
-2.59 0.53 -5.78 0.52
-1.54 0.58 -4.46 0.60


100.2 + 1.5


-2.98 0.19
-7.74 0.54
-7.92 0.70
-6.44 0.72
-4.58 0.68


Orlistat 120 mg TID
ITT Completer
N=210 N=117


100.5 + 0.98


-2.54 0.15
-8.0 0.58
-7.94 0.57
-6.22 0.62
-5.02 0.73


100.6 1.6


-3.03 0.25
-9.32 0.62
-8.78 0.73
-7.02 0.74
-5.16 0.78


ITT = intent-to-treat, N = number of patients


tested for compliance by having pills randomly
counted. If at least 75% compliance was shown,
obese patients with a BMI of 30-43 kg/m2 were ran-
domized to either prescription orlistat (120 mg), over
the counter orlistat (60 mg) or placebo. All three
groups were prescribed a reduced energy diet (5020
kJ/d in patients who weighed less than 90 kg initially
and 6275 kJ/d for patients who weighed 90 kg or
more initially) which was nutritionally balanced and
consisted of 30% energy as fat, 50% as carbohy-
drates, and 20% as protein, and contained a maxi-
mum of 300 mg/d of cholesterol. After the four-week
placebo lead-in period, the trial duration was 104
weeks in 17 primary care centers in the United
States. After the initial 52 weeks, patients received
the same treatment in combination with a weight
maintenance diet with the goal of preventing further
weight gain. Initially 796 patients were enrolled in
the study, but this number was reduced to 635 pa-
tients after the completion of the placebo lead-in pe-
riod. Statistically significant weight loss was seen in
both treatment groups compared with placebo
throughout the two-year study (p<0.01). Orlistat 120
mg showed the largest decrease in weight. Table 1
shows the changes in body weight from baseline
throughout the two-year period.

Orlistat 60 mg and 120 mg effect on weight loss and
cardiovascular risk factors
In a double-blind, placebo-controlled study,
the efficacy of orlistat 60 mg and orlistat 120 mg on
both weight as well as other cardiovascular risk fac-
tors such as dyslipidemia, hypertension, and diabetes


was evaluated.8 Patients included in the study were
men and women with a BMI of 28 to 43 kg/m2. The
study consisted of three treatment groups including
orlistat 120 mg, orlistat 60 mg, and placebo. After a
four-week placebo run-in period, which required
75% compliance, 729 of the original 754 patients
were randomized into one of three treatment groups.
All three groups were also counseled by a dietician
on a low energy diet that was designed to cause a
600 kcal daily energy deficit and were asked to keep
a food diary. All patients were followed by a dieti-
cian every two weeks for the first two months,
monthly up to month six, and then every two months
for the remainder of the study. After the four-week
placebo lead in period, there was a weight reduction
period of 52 weeks followed by a maintenance pe-
riod of 52 weeks. The primary outcome was change
in body weight over time. Secondary efficacy meas-
ures included changes in cholesterol levels, blood
pressure, fasting glucose, and insulin levels. Table 2
shows the efficacy of orlistat 60 mg and 120 mg in
both the intent-to-treat (ITT) population and com-
pleter populations compared to placebo. In the ITT
population, both orlistat 60 mg and 120 mg had a
statistically significant greater weight loss then pla-
cebo (p<0.001). There was not a statistically signifi-
cant decline in weight for patients treated with orl-
istat 60 mg when compared with placebo in the com-
pleter population.
Total cholesterol (p < 0.001), LDL-C (p <
0.001), and LDL/HDL ratio (p < 0.002) all declined
significantly in both orlistat treatment groups as
shown in Figure 1. A significant increase in HDL


PharmaNote Volume 22, Issue 12 September 2007


Volume 22, Issue 12 September 2007


PharmaNote







Table 2. Mean reduction in body weight for orlistat 60 mg, orlistat 120 mg, and placebos
Year 1 Year 2

Placebo Orlistat 60 mg Orlistat 120 mg Placebo Orlistat 60 mg Orlistat 120 mg

ITT (kg) 6.4 6.7 8.5 7.3* 9.4 6.4* 4.3 7.4 6.6 8.3* 7.4 7.1*
Completers (kg) 7.0 6.8 9.6 7.3 9.8 6.3* 4.3 7.5 6.8 8.4T 7.6 7.0*

ITT = intent-to-treat, p < 0.005 compared to placebo, p = 0.012 compared to placebo

was only achieved after year one in the orlistat 120 fat, 50% from carbohydrates, 20% as protein, no
mg group. Fasting blood glucose and diastolic blood more than 300 mg/day of cholesterol, and less than
pressure was significantly reduced after year one in 150 g/wk of alcohol. Men were allowed 1400 kcal/d
the higher dose orlistat group. Reductions in fasting and women 1200 kcal/d if they were less than 90 kg.
insulin were not seen until the end of year two and If they were greater than or equal to 90 kg, men were
only in the orlistat 120 mg group. Secondary out- allowed 1600 kcal/d and women were allowed 1400
comes were not significant in the placebo group. kcal/d. No diet counseling or dieticians were in-
volved in the study. Twenty different primary care
Orlistat 60 mg in overweight patients sites in the United States screened 498 people and
In a double-blind, placebo-controlled study, then randomized 391 patients. After two weeks, pa-
the efficacy of orlistat 60 mg on weight reduction in tients in the orlistat group had lost significantly more
mild to moderately overweight patients was as- weight than patients taking placebo (3.05 kg vs. 1.9
sessed.9 Patients included in the study were men and kg, p <0.001). Figure 2 shows the relative change in
women with a BMI between 25 and 28 kg/m2. The weight loss among the two groups.
study consisted of only two treatment groups receiv-
ing either orlistat 60 mg or placebo. The study did Adverse Reactions
not include a placebo run-in period and lasted only Because orlistat is minimally absorbed, the
16 weeks. All patients were instructed on maintain- incidence of systemic side effects is minimal. Gas-
ing a low energy diet that provided 30% energy from trointestinal (GI) side effects were the most com-


Figure 1. Mean % change in serum total and LDL cholesterol. Adapted from Rossner et al.8
10-
8 ---- Placebo
6- --- Orlistat 60 mg
4- Orlistat 120 mg
2-
0-



o-'-- 0 -10
Ol -2

1 -4 0 12 24 36 52
+ -- Placebo
S --Orlistat 60 mg
-4-
2- ----Orlistat 120 mg
0-
-2
-4-
-6- P< 0.001
-8-
-10-
-12-
-14-
-4 0 12 24 36 52
Week


Volume 22, Issue 12 September 2007


PharmaNote







Figure 2. Relative weight change (%) for orlistat 60 mg
compared to placebo. Adapted from Anderson et al.9

0-- Orlistat 60 mg
-0- Placebo
-1

-0
_ -2-
-

-3-
._i

S-4 +


-5


-6 --ii
0 4 8 12 16
Week of treatment
only observed in clinical trials. Table 3 shows the
incidence of gastrointestinal events of orlistat 60 mg
three times a day compared to orlistat 120 mg three
times a day and placebo. Although GI events oc-
curred in the orlistat treatment groups more fre-
quently than the placebo group, most GI events were
mild to moderate in intensity and occurred early dur-
ing treatment. Most patients experienced GI events
only one to two times during treatment. The pre-
scribing information states that eating a low-fat diet
decreases the chances of having bowel changes.10
Orlistat can affect absorption of fat soluble
vitamins such as vitamin A, D, and E and beta-
carotene. In clinical trials, two consecutive low vita-
min E and beta-carotene levels occurred more fre-
quently in the orlistat group than in placebo. Levels
of vitamin A and D did not differ between treatment

Table 3. Percentage of gastrointestinal adverse events7


groups. Upon supplementation, most patients re-
turned to within normal range.7 The prescribing in-
formation specifies when using OTC orlistat, vitamin
supplementation should be taken at bedtime.10

Dosing and Administration
OTC orlistat is a 60 mg capsule which is to
be taken with each fat containing meal, not to exceed
3 capsules per day. Clinical trials evaluated the effi-
cacy of OTC orlistat only when used with a well-
balanced, reduced calorie, low fat diet and regular
exercise. Patients should be encouraged to exercise
and follow this diet in order to optimize the efficacy
of OTC orlistat as well as reduce the amount of gas-
trointestinal side effects.
OTC orlistat is only indicated in overweight
adults who are 18 years old or older. Clinical trials
evaluating the safety and efficacy of the 120 mg dose
of orlistat in adolescence are underway.11 OTC orl-
istat should not be used in patients with problems
absorbing food, patients who are not overweight, as
well as patients who have undergone an organ trans-
plant because OTC orlistat has been shown to inter-
act with cyclosporine.10 Cyclosporine absorption is
lipid dependent and is therefore inhibited by gastro-
intestinal lipase inhibitors.5 Patients should check the
height/weight chart in the label of OTC orlistat be-
fore initiating treatment to verify that they are actu-
ally overweight. The height/weight chart shown in
Figure 3 shows the weight patients should be at or
above for their height before being considered over-
weight and eligible to take OTC orlistat.10

Cost
OTC orlistat is available at any community
pharmacy, grocery store, or anywhere where weight
loss products are sold. OTC orlistat can also be pur-


Event* Placebo (%) Orlistat 60 mg TID (%) Orlistat 120 mg TID (%)
Fecal urgency 6.6 22.5 25.2
Oily spotting 1.4 20.2 24.3
Fatty/oily stool 3.3 22.5 23.8
Flatus with discharge 2.4 25.4 18.1
Oily evacuation 0.0 12.2 11.0
Increased defecation 1.9 9.9 11.0
Fecal incontinence 0.9 6.1 6.7
*All events occurred more frequently in both orlistat treatment groups compared with placebo (P 0.001). TID= 3 times daily

PharmaNote 4 Volume 22, Issue 12 September 2007







Figure 3. Weight/height consideration for OTC orlistat

Ht. / t.
4' 10" 129 Ibs.
4'11" 133 Ibs.
5' 0" 138 Ibs.
5'1" 143 Ibs.
5' 2" 147 Ibs.
5' 3" 152 Ibs.
5' 4" 157 Ibs.
5' 5" 162 Ibs.
5'6" 167 Ibs.
5'7" 172 Ibs.
5' 8" 177 Ibs.
5' 9" 182 Ibs.
5' 10" 188 Ibs.
5'11" 193 Ibs.
6' 0" 199 Ibs.
6' 1" 204 Ibs.
6'2" 210 Ibs.
6'3" 216 Ibs.
6' 4" 221 Ibs.
6' 5" 227 Ibs.

chased online. First time users are encouraged to pur-
chase the starter pack, which includes medication, a
carrying case, and seven reference guides.12 The
starter pack comes with 90 capsules or 60 capsules
which cost approximately $60.00 or $50.00.13 After
initiating OTC orlistat, the patient is encouraged to
buy the refill packs which include the medication
and the Read Me First Guide.12 The Read Me First
Guide includes helpful tips for patients to use in or-
der to follow their weight loss plan. The refill pack
contains 120 capsules and costs approximately
$70.00.13

Summary
OTC orlistat is a 60 mg dose of orlistat that is
now available over-the-counter. Orlistat works as a
reversible lipase inhibitor which inhibits the absorp-
tion of fat. OTC orlistat is to be taken with each fatty
meal up to three times daily and has been shown to
be more beneficial than diet alone for both weight
loss as well as reduction of other cardiovascular risk
factors such as dyslipidemia. Gastrointestinal side
effects may occur when taking OTC orlistat, but are
reduced when the patient adheres to a low fat diet.
OTC orlistat is an option for patients 18 years or
older who have failed to lose weight by diet and ex-
ercise alone.

References
1. Center for Disease Control and Prevention.
"Overweight and Obesity." Department of Health and
Human Services. www.cdc.gov Accessed 22 May
2007
2. National Heart, Lung and Blood Institute Clinical
Guideline on the Identification, Evaluation, and


Treatment of Overweight and Obesity in Adults; Obe-
sity Education Initiative. 1998.
3. Mele J, Salrhoot T, Nevius E. Statistical Review and
Evaluation. Center for Drug Evaluation and Research.
U.S. Department of Health and Human Services.
Food and Drug Administration.
4. Centers for Disease Control. Cardiac valvulopathy
associated with exposure to fenfluramine or dexfen-
fluramine. MMWR 1997; 46: 1061-5
5. Clinical Pharmacology. CopyrightC 2007, Gold Stan-
dard Inc.
6. Micromedex Healthcare Series, (electronic version).
Thomson Micromedex, Greenwood Village, Colo-
rado, USA. Available at: http://www.thomsonhc.com
7. Haupten J, Lucas C, Boldrin M, et al. Orlistat in the
long-term treatment of obesity in primary care set-
tings. Arch Fam Med 2000; 9: 160-7.
8. Rossner S, Sjostrom L, Noack R, et al. Weight loss,
weight maintenance, and improved cardiovascular
risk factors after 2 years treatment with orlistat for
obesity. Obesity Research 2000; 8: 49-61.
9. Anderson, JW, Schwartz, SM, Hauptman, J., et al.
Low-dose orlistat effects on body weight of mildly to
moderately overweight individuals: a 16 week, dou-
ble-blind, placebo-controlled trial. Ann Pharmacother
2006;40:1717-23.
10. Alli [package insert]. Moon Township, PA. Glaxo
Smith Kline; 2007.
11. National Library of Medicine. Safety and efficacy of
xenical in children and adolescents with obesity-
related diseases. www.clinicaltrials.gov Accessed 23
May 2007
12. GlaxoSmithKline. "What is Alli?" www.myalli.com;
Accessed 22 May 2007
13. CVS/pharmacy. "Product Prices." www.cvs.com;
Accessed 23 May 2007


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

Shawn Anderson Assistant Editor
Pharm.D.


Pharma~~~~~~~t4=3 Voue2,Ise12Spebr20


Volume 22, Issue 12 September 2007


PharmaNote




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