DRUG FORECAST
Advances in Proton Pump Inhibitor
Therapy: An Immediate-Release
Formulation of Omeprazole
Ralph E. Small, PharmD
PROTON PUMP INHIBITORS:
AN OVERVIEW
Acid-related disorders encompass a
wide variety of diagnoses, including the
extremely prevalent gastroesophageal
reflux disease (GERD), which affects an
estimated 25 million Americans,1 duo-
denal and gastric ulceration, stress-
related mucosal disease, and acute upper
gastrointestinal bleeding, a common
medical emergency resulting in approx-
imately 300,000 hospitalizations annu-
ally.2 During the last three decades, the
management of these disorders has been
revolutionized by the introduction of his-
tamine-2 receptor antagonists (H2RAs)
and proton pump inhibitors (PPIs).
Five available delayed-release PPIs
include omeprazole (Prilosec®, Astra-
Zeneca), lansoprazole (Prevacid®, TAP),
pantoprazole (Protonix®, Wyeth), eso-
meprazole magnesium (Nexium®, Astra-
Zeneca), and rabeprazole (Aciphex ®,
Eisai/Janssen). These drugs are highly
effective, irreversible inhibitors of H+/K+
ATPase, the final step in gastric acid
secretion.
Although these agents form the thera-
peutic cornerstone of management for a
variety of acid-related disorders, there is
still room for improvement in our arma-
mentarium. For example, all PPI com-
pounds are weak bases that are acid-
labile and are rapidly degraded, usually
within minutes, in the acidic environment
of the stomach. Until the recent intro-
duction of immediate-release omeprazole
Dr. Small is Professor Emeritus at Virginia
Commonwealth University in Richmond, Vir-
ginia. Drug Forecast is a regular department
coordinated by Alan Caspi, PhD, PharmD,
MBA, President of Caspi & Associates in New
York.
698 P&T® • December 2005 • Vol. 30 No. 12
(IR-OME [Zegerid ®, Santarus]), this
pharmacological property required the
active ingredient in all delayed-release
oral PPI formulations to have an enteric
coating. The coating protects the active
ingredient from degradation by gastric
acid, but it also delays absorption, so that
the peak plasma concentration (Cmax) is
not typically attained for up to five hours
after oral administration of these formu-
lations. In addition, patients must not
chew or crush the tablets or the enteric-
coated granules.
For patients who cannot swallow
intact capsules or tablets or who have a
nasogastric tube in place, various liquid
formulations have been compounded ex-
temporaneously from sodium bicarbon-
ate solution, with omeprazole or lanso-
prazole granules, or crushed panto-
prazole tablets.3,4 These formulations
have a limited shelf life and may adhere
to the syringe and the tubing used for ad-
ministration, with the result that the tub-
ing has the potential to become clogged.5
Limitations to enteric-coated PPI for-
mulations also include the potential for
nocturnal acid breakthrough (NAB),
defined as an intragastric pH below 4 for
at least one hour during the night with
PPI therapy. NAB occurs in up to 70% of
patients with GERD.6–9 Despite adequate
therapeutic dosing (including twice-daily
administration), patients taking enteric-
coated, delayed-release PPIs may expe-
rience nocturnal gastric acidity, whether
or not the agent is taken before breakfast,
before dinner, or twice daily9–11 and may
have nighttime symptoms of heartburn.
Patients with nocturnal GERD may have
a higher potential for severe reflux-
induced complications such as esophagi-
tis, Barrett’s esophagus, esophageal
motility disorder, esophageal stricture
formation, and esophageal adeno-
carcinoma.9,12–17 Individuals with noc-
turnal heartburn also report less satis-
faction with PPIs and a diminished
quality of life in terms of both mental and
physical components, compared with
GERD patients, who do not experience
nocturnal heartburn.7,18
Strategies for managing nocturnal
gastric acidity include increasing PPI
administration from once to twice daily,
increasing the dose, switching to another
PPI, or adding an H2RA at bedtime.19–21
Although this last strategy may provide
short-term efficacy, its clinical utility may
be limited by the potential for the devel-
opment of tolerance to H2RAs as well as
by the additional cost of therapy.
Lapses in controlling gastric pH during
PPI therapy may impair the ability of
PPIs to adequately protect against stress-
related intestinal mucosal disease, a
significant clinical problem that occurs in
70% to 90% of critically ill patients22 and
portends increased morbidity as well as
extended hospital stays. 23–26 Among
patients who are not given prophylactic
pharmacological therapy, overt upper
gastrointestinal (GI) bleeding has been
documented in 17% of critically ill
patients.23
More than a decade ago, investigators
found that various degrees of acid sup-
pression produced different physiologi-
cal effects in the gastric milieu.23 At a pH
of 4.5 or above, pepsin begins to be
inactivated; at a pH of 5 or above, it
becomes completely inactivated; and at a
pH of 7 or above, there is a potential for
a decreased incidence of peptic ulcer
rebleeding in patients who have already
achieved hemostasis.23
Some investigators suggest that a
gastric pH of 6.5 or higher is optimal for
preventing stress ulceration; at this value,
pepsin is inactivated and blood coag-

Table 1 Uses and Dosages of Immediate-Release Omeprazole
(IR-OME) Powder for Suspension
Indication
1. Short-term treatment of active
duodenal ulcer
2. Gastric ulcer
3. GERD; symptomatic, no
esophageal lesions
4. GERD; symptomatic with confirmed
erosive esophagitis
5. Maintenance of healing of
erosive esophagitis
6. Reduction in risk of upper
gastrointestinal bleeding in critically
ill patients
GERD = gastroesophageal reflux disease.
ulation parameters are maintained, 22
although other authors consider a pH of
3.5 to 4 or above to be sufficient.23,27,28
H2RAs can be effective in attaining these
levels, but tachyphylaxis is a frequent
occurrence.29 More recent studies sup-
port the clinical efficacy of PPI therapy in
the management of these critically ill
patients;30–33 a recent Cochrane Collabo-
ration found that the ability of PPI therapy
to raise gastric pH is independent of the
route of administration;31 however, this
effect must be sustainable.
Therefore, although significant prog-
ress has been made in treating acid-
related disorders, patients would benefit
from advances in PPI therapy. Specifi-
cally, an acid-suppressing agent that
shows more rapid absorption; that can
be administered orally, even in patients
who cannot swallow intact capsules or
tablets; that provides better nocturnal
acid control; and that sustains gastric pH
above a critical threshold would be a wel-
come addition to the PPI class.
THE ADVENT OF IMMEDIATE-
RELEASE OMEPRAZOLE
Approximately one year ago, the U.S.
Food and Drug Administration (FDA)
approved a unique IR formulation of
omeprazole (Zegerid®) to treat a variety
of acid-related disorders and to reduce the
Dose
1. 20 mg once daily for four weeks;
some patients may require an
additional four weeks of therapy.
2. 40 mg once daily for four to eight
weeks.
3. 20 mg once daily for up to four
weeks
4. 20 mg once daily for four to eight
weeks
5. 20 mg once daily; controlled studies
do not extend beyond 12 months.
6. 40 mg initially, followed by 40 mg
after six to eight hours as a loading
dose on the first day, then 40 mg
once daily for up to 14 days; the use
of IR-OME in critically ill patients
for longer than 14 days has not been
evaluated.
risk of upper gastrointestinal bleeding in
critically ill patients (Table 1). This com-
pound was developed by combining a
highly effective PPI (omeprazole) with an
antacid buffer (sodium bicarbonate),
which neutralizes gastric acid and protects
the PPI from gastric acid degradation.
Studies have found that the degrada-
tion half-life of non–enteric-coated ome-
prazole is approximately seven hours at
a pH of 6, compared to less than three
minutes at a pH of 1.2.34 In an in vitro
model, the sodium bicarbonate buffer in
IR-OME rapidly increases the pH to
greater than 6 within one minute and sus-
tains this pH environment for approxi-
mately 30 minutes.41 This pharmacolog-
ical synergy protects omeprazole from
gastric acid degradation, allows it to be
rapidly absorbed, and eliminates the
need for an enteric coating.
PHARMACOKINETICS
The pharmacokinetic profile of IR-
OME differs significantly from that of a
delayed-release PPI plus an antacid.
Specifically, the Cmax of the IR formula-
tion is achieved in 10 to 90 minutes
(mean, 30 minutes) after single or multi-
ple oral doses are taken on an empty
stomach.35 In contrast, several investiga-
tors, studying the pharmacokinetics of
delayed-release omeprazole or rabepra-
zole, coadministered with antacids, found
DRUG FORECAST
no significant change in the Cmax, the
mean time to peak plasma concentration
(T max ), or the area under the curve
(AUC).36–39 One study of delayed-release
lansoprazole, given with an antacid,
revealed a slight decrease in the AUC
and a significant decrease in the Cmax
with no change in the Tmax.40
In an open-label, randomized, two-
period crossover comparator trial with a
10- to 14-day washout period between
treatments, IR-OME in strengths of 40
and 20 mg was compared with delayed-
release 40- and 20-mg omeprazole cap-
sules.35,41 During each treatment period,
healthy subjects received seven consec-
utive single daily doses of each dosage
strength one hour before they ate a stan-
dardized high-fat breakfast.
As illustrated in Figure 1, the Tmax
observed with each dosage strength of
the IR formulation occurred much
sooner (P < .001) (at approximately 30
minutes with each dose) than that of the
respective dose of the enteric-coated for-
mulation (at 1.8 and 1.4 hours, respec-
tively) with delayed-release omeprazole
40 mg and 20 mg (Table 2).
The AUC of IR-OME 40 mg is about
three-fold higher than that of the 20-mg
dose, and repeated exposure to the IR
form results in increased bioavailability.
The observed increase in the AUC is
almost doubled from a single dose, com-
pared with the steady state (Table 2A).35
Because taking IR-OME one hour after a
meal decreases the AUC by approxi-
mately 26% at steady state, optimal phar-
macokinetic parameters are achieved
when patients take this drug on an empty
stomach. However, the AUC associ-
ated with a postprandial 40-mg dose of
IR-OME is still substantial (3,862 ng •
hour/ml) in the range associated with
a 70% reduction in baseline gastric
acidity.35
Approximately 95% of omeprazole is
protein-bound. In healthy subjects, its
plasma half-life is about one hour (range,
0.4–3.2 hours) and the plasma clearance
averages between 500 and 600 ml/
minute. Most of the omeprazole (77%) is
excreted as metabolites in the urine, and
the remainder is eliminated in the
feces.35
Elderly Populations
Older age produces a slight decrease
in the elimination rate of omeprazole and
Vol. 30 No. 12 • December 2005 • P&T® 699
DRUG FORECAST

tive mucosal healing.42 Studies in healthy

Table 2 Mean Pharmacokinetic Parameters after Administration subjects have found that once-daily
of Omeprazole on Days One and Seven dosing of 40 mg and 20 mg of IR-OME
A, Immediate-Release Omeprazole maintains the gastric pH above 4 for
Day One Day Seven 77% and 51%, respectively, of a 24-hour
Parameter 40 mg 20 mg 40 mg 20 mg period.35,43 In these two studies, IR-OME
maintained a median gastric pH of 5.2
AUC0–∞ (ng • hour/ml) 2,228 825 4,640 1,446 with the 40-mg dose and 4.2 with the
Cmax (ng/ml) 1,412 672 1,954 902 20-mg dose. 35,43 The median 24-hour
Tmax (minutes) 26.6 29.8 34.7 28.3 gastric pH exceeded 4 for 18.6 hours with
Half-life (hours) 1.00 0.86 1.38 1.08 40 mg and 12.2 hours with 20 mg. The
decrease from baseline for integrated
B, Delayed-Release Omeprazole gastric acidity (or total accumulated
Day One Day Seven gastric acid) with IR-OME 40 mg was
Parameter 40 mg 20 mg 40 mg 20 mg 84%; with 20 mg, the decrease was 82%.
Although no head-to-head studies have
AUC0–∞ (ng • hour/ml) 2,658 903 4,591 1,351 compared IR-OME with delayed-release
Cmax (ng/ml) 1,040 461 1,677 573 esomeprazole, lansoprazole, or rabepra-
Tmax (hours) 2.34 1.74 1.77 1.39 zole, the duration of time that IR-OME
Half-life (hours) 1.21 1.21 1.42 1.30 40 mg and 20 mg maintain the gastric
AUC = area under the curve; Cmax = maximum concentration; Tmax = time to maximum pH above 4 is slightly longer than the
concentration. values reported in the product labeling
for these delayed-release compounds
increases its bioavailability. Compared and plasma clearance decreases to about (Table 3).35,44–47 In all cases, given the
with a bioavailability of 58% in younger 70 ml/minute.35 relatively short plasma half-lives of these
subjects, the bioavailability of a single medications (about one hour), the
40-mg dose of IR-OME in healthy older Renal Impairment extended durations of antisecretory
subjects was 76%.35 The extent of metabo- In patients with chronic renal impair- effects probably reflect the irreversible
lite excretion in the urine (70%) was sim- ment (the creatinine clearance is binding to the parietal cell H+/K+
ilar to that observed in younger subjects. between 10 and 62 ml/minute per 1.73 ATPase enzyme by the PPIs.
The plasma half-life was also similar at m2), the bioavailability of omeprazole is
approximately one hour.35 slightly increased and urinary elimina- CLINICAL TRIALS
tion is decreased. The reduced elim- Efficacy
Hepatic Impairment ination is related to the decrement in Nocturnal Acid Control
In patients with chronic hepatic dis- creatinine clearance.35 One trial has confirmed the effective-
ease, the bioavailability of IR-OME ness of a bedtime dose of IR-OME in
increases, reflecting a decrease in first- PHARMACODYNAMICS controlling nocturnal gastric acidity.
pass metabolism. The plasma half-life A gastric pH of greater than 4 has long Goldlust and colleagues43 presented data
increases to approximately three hours, been established as the target for effec- from an open-label study. IR-OME 20 mg

1,800 – Immediate-release omeprazole suspension 40 mg 1,800 – Immediate-release omeprazole suspension 40 mg

– –
Plasma Concentration (ng/ml)

1,600 Immediate-release omeprazole suspension 20 mg 1,600

Plasma Concentration (ng/ml)

Immediate-release omeprazole suspension 20 mg

1,400 – Delayed-release omeprazole capsule 40 mg 1,400 – Delayed-release omeprazole capsule 40 mg

1,200 – Delayed-release omeprazole capsule 20 mg 1,200 – Delayed-release omeprazole capsule 20 mg

1,000 – 1,000 –

800 – 800 –

600 – 600 –

400 – 400 –

200 – 200 –

0– 0–
I I I I I I I I I I I I I I I I I I
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
A Day 1 Hours B Day 7 Hours

Figure 1 A, B, Mean plasma concentrations of immediate-release omeprazole (IR-OME) suspension and delayed-release omepra-
zole capsules on days one and seven. Both compounds were administered one hour before mealtime. The mean time to peak plasma
concentration (Tmax) with these doses occurred significantly sooner (at approximately 30 minutes) (Table 2A) on days one and seven
than that of delayed-release omeprazole (range, 1.7–2.3 hours) on day one (Table 2B) and with a repeated administration (range,
1.4–1.8 hours) on day seven (Table 2B). (Data from Santarus.35,41)

700 P&T® • December 2005 • Vol. 30 No. 12

 DRUG FORECAST

Table 3 Pharmacodynamic Parameters of Proton Pump Inhibitors by Product Labeling

IR-OME Esomeprazole Lansoprazole Rabeprazole Pantoprazole
(Zegerid®) (Nexium®) (Prevacid®) (Aciphex®) (Protonix®)
40 mg 20 mg 40 mg 20 mg 30 mg 15 mg 20 mg 40 mg 20 mg
Time gastric 18.6 12.2 16.8 12.7 15.8 11.7 14.4 NA NA
pH > 4 (hours)
Percentage of time 77% 51% 70% 53% 66% 49% 60% NA NA
with gastric pH > 4
Median gastric pH 5.2 4.2 4.9* 4.1* 4.9* 4.0* 3.5 3.8 2.9
IR-OME = immediate-release omeprazole; NA = not available.
* Mean.
Data from package inserts.35, 44–47

was administered once a day one hour
before breakfast for seven days to 17
healthy subjects. On the eighth day, the
participants received IR-OME 20 mg
twice daily, one hour before breakfast
and at bedtime (10 p.m., or 2200 hours).
Twenty-four-hour gastric pH monitoring
was performed on days seven and eight.
Figure 2 depicts the 24-hour median
gastric pH profiles of patients taking
IR-OME at the steady state with 40 mg
once daily in the morning, 20 mg once
daily in the morning, and 20 mg twice
daily, in the morning and at bedtime. As
shown in Figure 2C, the bedtime dose of
IR-OME rapidly raised the gastric pH and
sustained this effect for approximately
eight hours. The median percentage of
nighttime hours during which the gastric
pH was above 4 was 87% with twice-daily
dosing of 20 mg and 39% with once-daily
morning dosing of 20 mg of IR-OME
(P < .001).43 Twice-daily administration of
20 mg of IR-OME also significantly
reduced the percentage of patients with
NAB, compared with 20 mg administered
once daily in the morning, namely, 29%
(five of 17 patients) versus 76% (13 of 17
patients) (P = .005).43
Castell and colleagues compared the
nighttime gastric pH control of IR-OME
suspension with that of delayed-release
pantoprazole tablets.48 (Pantoprazole is
currently the only PPI that is FDA-
approved to treat nighttime symptoms of
GERD.) In the first period of the open-
label, two-period crossover trial, patients
with a history of nocturnal GERD symp-
toms were randomly assigned to receive
either IR-OME or pantoprazole. IR-OME
40 mg (n = 32) was taken at bedtime
(10 p.m.) for six days. On day seven, 15
patients were randomly selected to
receive IR-OME 20 mg twice daily, one
hour before breakfast and at bedtime; 17
patients received IR-OME 40 mg twice
daily, also one hour before breakfast and
at bedtime.
Pantoprazole 40 mg was administered
at 10 p.m. on day one and before dinner
on days two through six. On day seven,
this dose was given twice: one hour
before breakfast and at bedtime). After a
10- to 14-day washout period, patients
“crossed over” to the alternate treatment
in the second period.
As illustrated in Figure 3, statistically
significant differences (P < .001) were
observed between the once-daily and
twice-daily IR-OME suspensions and the
comparative pantoprazole regimen in the
median percentages of time that the
gastric pH was maintained above 4 dur-
ing the eight-hour nighttime interval
(from 10 p.m. to 6 a.m.). For each paired
comparison, the median values were as

Fig 2A. Trial 1 – 40 mg q AM Day 7 (Dose 7) Fig 2B. Trial 2 – 20 mg q AM Day 7 (Dose 7) Fig 2C. Trial 2 – 20 mg q AM and HS Day 8 (Doses 8 and 9)
Dose Meal Meal Meal Dose Meal Meal Meal Dose Meal Meal Meal Dose
8 8 8

7 7 7

6 6 6
Gastric pH
Gastric pH

Gastric pH

5 5 5

4 4 4

3 3 3

2 2 2

1 1 1
n = 24 n = 17 n = 17
0 0 0
0830 1130 1430 1730 2030 2330 0230 0530 0830 0830 1130 1430 1730 2030 2330 0230 0530 0830 0830 1130 1430 1730 2030 2330 0230 0530 0830
Hours (24-hour Clock) Hours (24-hour Clock) Hours (24-hour Clock)

Figure 2 A, B, Twenty-four-hour gastric pH profiles of immediate-release omeprazole (IR-OME). Repeated administration of

IR-OME in the morning produces a gastric acidity profile similar to other proton pump inhibitors (PPIs). C, Adding a second bed-
time dose of IR-OME abruptly raises the gastric pH and sustains this level throughout the nighttime interval. HS = at bedtime.
(From Goldlust B, Hepburn B, Hardiman Y. Am J Gastroenterol 2004;99:S39.43)

Vol. 30 No. 12 • December 2005 • P&T® 701

DRUG FORECAST

placebo) or IV cimetidine (Tagamet®,

P < .001
GlaxoSmithKline), given as a 300-mg
100 P < .001 P < .001
92.0% bolus. This dose was followed by an
infusion of 50 mg/hour thereafter (and
80 78.5%
placebo oral suspension). Each regimen
% Time pH > 4

60 54.7% was administered for up to 14 days.

36.5% Gastric aspirates were sampled for
40 31.3%
26.5% upper GI bleeding every two hours on
20 the first and second days, then every six
hours for the remaining study days.
0
IR-OME Pantoprazole IR-OME Pantoprazole IR-OME Pantoprazole Gastric aspirates were also used to meas-
40 mg q.d. 40 mg q.d. 20 mg b.i.d. 40 mg b.i.d. 40 mg b.i.d. 40 mg b.i.d. ure pH every two hours on the first and
(n = 32) (n = 32) (n = 15) (n = 15) (n = 17) (n = 17) second days and immediately before and
one hour after administration of the
IR-OME suspension on days 3 to 14. The
Figure 3 Median percentage of time that gastric pH stayed above 4 during the night-
dose of IR-OME or cimetidine was dou-
time interval (from 10 p.m. to 6 a.m.) following repeated dosing with immediate-
bled for patients with two successive
release omeprazole (IR-OME) and pantoprazole. For this eight-hour interval, the me-
gastric aspirates of a pH of 4 or less. A
dian time that gastric pH stayed above 4 was significantly greater with IR-OME once
second daily dose of IR-OME 40 mg was
daily (q.d.) or twice daily (b.i.d.), compared with pantoprazole once daily (P < .001 for
administered to patients only on the day
each comparison). (Data from Castell D, et al. Aliment Pharmacol Ther 2005;21:
when they had two successive gastric
1467–1474.48)
aspirates of a pH of 4 or less, whereas the
shown in Figure 3. upper GI bleeding in critically ill patients dose of cimetidine was doubled to 100
The median nighttime gastric pH val- in a multicenter, randomized, double- mg/hour for the duration of the study.
ues were 4.7 with IR-OME 40 mg and blind, double-dummy, parallel-group Patients were permitted enteral feedings
2 with pantoprazole 40 mg on day six study of 359 patients.49 These patients, after the third day. Feedings were held
(P < .001).48 who were undergoing mechanical venti- for three hours before and for one hour
The percentage of patients who ex- lation in the intensive care unit (ICU) after administration of the IR-OME sus-
perienced NAB was also significantly and had Acute Physiology and Chronic pension.
smaller during IR-OME therapy than Health Evaluation II (APACHE II) scores The primary efficacy endpoint of this
with pantoprazole on days six and seven of 11 or higher and one additional risk non-inferiority study was the occurrence
(P < .005 for each comparison) (Figure factor for upper GI bleeding, were en- of clinically significant upper GI bleed-
4). On day six, significantly fewer patients rolled at 47 sites in the U.S. ing. This was defined as bright-red blood
treated with IR-OME 40 mg (53.1%) ex- The patients were assigned to receive via a nasogastric or an orogastric tube
perienced NAB than when they had used either IR-OME suspension via naso- that had not cleared after 5 to 10 minutes
pantoprazole 40 mg (78.1%) (P = .005). gastric or orogastric tube at a dose of 40 of lavage or as persistent Gastroccult®-
Twice-daily IR-OME produced a sig- mg twice daily on day one (six to eight positive coffee-ground material for at
nificantly higher median percentage of hours apart) and 40 mg once daily there- least eight consecutive hours on days one
time during which the gastric pH was after (and continuous intravenous [IV] and two or for two to four hours on days
maintained above 4, compared with
twice-daily pantoprazole during the P = .005 P = .002
100
24-hour interval (10 p.m. to 10 p.m.).
Percentage of Patients

A median gastric pH level greater than 80 78.1% 70.6%

4 was maintained for 87.8% of the 24-hour
60 53.1%
interval with twice-daily IR-OME 40 mg,
compared with 56.9% (P < .001) observed 40
during twice-daily therapy with panto-
20 11.8%
prazole 40 mg.48
At steady state, the median percentage 0
IR-OME Pantoprazole IR-OME Pantoprazole
of time with the gastric pH above 4 during
40 mg q.d. 40 mg q.d. 40 mg b.i.d. 40 mg b.i.d.
the 24-hour interval was similar for paired at bedtime before dinner (n = 17) (n = 17)
patients taking once-daily IR-OME 40 mg (n = 32) (n = 32)
and twice-daily pantoprazole 40 mg (Fig-
ure 5).48
Figure 4 Percentage of patients with nocturnal acid breakthrough (NAB) during treat-
Reduction in Risk of Upper GI ment with immediate-release omeprazole (IR-OME) and pantoprazole. IR-OME once
Bleeding in Critically Ill Patients daily (q.d.) and twice daily (b.i.d.) produced significantly smaller percentages of patients
Conrad and colleagues established the with NAB (P < .005), compared with pantoprazole once or twice daily. (Data from
efficacy of IR-OME in reducing the risk of Castell D, et al. Aliment Pharmacol Ther 2005;21:1467–1474.48)
continued on page 711

702 P&T® • December 2005 • Vol. 30 No. 12

 DRUG FORECAST
continued from page 702
100
whom were white, were treated for a IR-OME and cimetidine were similar. For
mean of 6.8 days. Patient characteristics instance, nosocomial pneumonia
% Time pH > 4

80 61.1%
60
40
20
0
IR-OME
40 mg q.d.
(n = 18)
Figure 5 Median percentage of time that
the gastric pH stayed above 4 during
the 24-hour interval following repeated
dosing with immediate-release omepra-
zole (IR-OME) and pantoprazole. A
median gastric pH above 4 was main-
tained for 61.1% of the 24-hour interval
for once-daily (q.d.) IR-OME 40 mg,
compared with 56.2% for pantoprazole
40 mg twice daily (b.i.d). (Data from
Castell D, et al. Aliment Pharmacol Ther
2005;21:1467–1474.48)
3 through 14 that had not cleared with
100 ml or more of lavage. Because this
was a non-inferiority study, the primary
efficacy analysis was conducted on the
per-protocol population at the one-sided
α = 0.025 level of significance.
Secondary endpoints included the per-
centage of patients with any evidence of
bleeding and the percentage of patients
with a gastric pH of 4 or below on two
consecutive gastric aspirates. The safety
and tolerability of each regimen were also
assessed.
The mean patient age was 55.7 years
(range, 16–91 years). These patients,
58.5% of whom were men and 64% of
56.2%
were similar between the treatment
groups.49
The rates of clinically significant bleed-
Pantoprazole ing were 4.5% with IR-OME and 6.8% with
40 mg b.i.d. cimetidine. These results satisfied the
(n = 18) criteria for the non-inferiority of IR-OME
in preventing upper GI bleeding in criti-
cally ill patients compared with IV cime-
tidine. IR-OME was more effective than
IV cimetidine in maintaining a median
gastric pH above 4.0 in critically ill
patients.
The effects of IR-OME on gastric pH
were consistent regardless of patients’
baseline pH values. Median gastric pH
values greater than 6 were observed in al-
most all patients following the first dose
of IR-OME. A median gastric pH above 6
was sustained on all days for patients re-
ceiving IR-OME but persisted on only
50% of the days for patients receiving
cimetidine (Figure 6).
After three days of cimetidine admin-
istration, the median gastric pH began to
decline, suggesting the development of
tachyphylaxis. After day eight, at least
25% of the cimetidine patients had a
median gastric pH below 4. During the
entire trial, failure of pH control (two con-
secutive gastric aspirates of pH of 4 or
below at least one hour apart on the same
day) was observed in 58% of the cimeti-
dine patients but in only 18% of the IR-
OME patients (P < .001).
The incidence and type of adverse
drug events (ADEs) reported with
occurred at a rate of 11.2% with IR-OME
and at a rate of 9.4% with IV cimetidine
(P = .61).49
All currently available PPIs, including
IR-OME, are effective in relieving GERD
symptoms, healing gastroduodenal ul-
cers, providing treatment of erosive
esophagitis, and maintaining healing of
lesions. Unlike the other PPIs, IR-OME
may control nocturnal gastric acidity
when it is given at bedtime.
IR-OME is the only PPI that has been
subjected to clinical study and carries an
FDA indication for reducing the risk of
upper GI bleeding in critically ill
patients.
Safety
Adverse Effects
In the U.S. trial of omeprazole, the
most frequently reported ADEs in 465
patients that were considered possibly,
probably, or definitely treatment-related
were headache (in 2.4% of patients),
diarrhea (in 1.9%), rash (in 1.1%), nausea
(in 0.9%), constipation (in 0.9%), dizzi-
ness (in 0.6%), vomiting (in 0.4%), ab-
dominal pain (in 0.4%), and asthenia (in
0.2%).
Occasional cases of atrophic gastritis
have been noted in gastric corpus biop-
sies of patients receiving long-term
omeprazole therapy.
A symptomatic response to omepra-
zole does not preclude the presence of
gastric malignancy.35

11
No. of patients
10
166 170 143 124 109 89 73 60 53 43 40 35 31 27 Immediate-Release Omeprazole
9
Median Gastric pH

8
7
6
5
4
3 No. of patients
2 174 175 157 122 103 88 78 70 59 51 46 39 33 28 Cimetidine
1
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Trial Day

Figure 6 Gastric pH in critically ill patients, by treatment. A median gastric pH above 6 was sustained on all days in patients
receiving immediate-release omeprazole (IR-OME) compared with 50% of the days in patients receiving cimetidine. (Adapted
from Conrad S, Gabrielli A, Margolis B, et al. Crit Care Med 2005;33[4]:760–765, Lippincott Williams & Wilkins.49)

Vol. 30 No. 12 • December 2005 • P&T® 711

DRUG FORECAST
Sodium Bicarbonate
Each 40-mg and 20-mg dose packet of
IR-OME contains 460 mg of sodium in
the form of sodium bicarbonate (1,680
mg, 20 mEq). This fact should be taken
into consideration for patients who are
following sodium-restricted diets. The
use of IR-OME is contraindicated in
patients with metabolic alkalosis and
hypocalcemia. Sodium bicarbonate
should also be used with caution in
patients with Bartter’s syndrome, hypo-
kalemia, respiratory alkalosis, and
acid–base imbalances.
The long-term administration of
sodium bicarbonate with calcium or milk
can induce the milk-alkali syndrome.35
DRUG INTERACTIONS
Like the delayed-release, enteric-
coated, oral PPI formulations, IR-OME
may prolong the elimination of drugs that
are metabolized by oxidation in the liver,
such as diazepam (Valium ®, Roche),
warfarin (Coumadin ®, Bristol-Myers
Squibb), and phenytoin (Dilantin®, Pfi-
zer). Increased International Normalized
Ratios (INRs) and prothrombin times
have been reported in patients receiving
concomitant warfarin and omeprazole
therapy. These increases may lead to
abnormal bleeding and possibly death.
Therefore, patients taking warfarin and
omeprazole concomitantly should be
monitored closely for INRs and pro-
thrombin times.35
In studies of once-daily omeprazole
40 mg and clarithromycin (e.g., Biaxin®,
Abbott) 500 mg every eight hours ad-
ministered to healthy men, the steady-
state plasma concentrations of omepra-
zole were increased: the Cmax by 30%, the
AUC 0–24 by 89%, and the half-life by
34%).35
INDICATIONS
As summarized in Table 1, IR-OME is
indicated for the short-term treatment
(four to eight weeks) of active duodenal
ulcer, heartburn, and other symptoms
associated with GERD; the short-term
treatment of erosive esophagitis, as
diagnosed by endoscopy; the mainte-
nance of healing of erosive esophagitis
(studies do not extend beyond 12
months); and the short-term treatment
of active benign gastric ulcer.35 This is the
only PPI to date that is indicated for low-
ering the risk of upper GI bleeding in
712 P&T® • December 2005 • Vol. 30 No. 12
critically ill patients and for nasogastric
and/or orogastric tube administration.35
DOSAGE AND ADMINISTRATION
The recommended dose of IR-OME
is 40 mg or 20 mg, based upon the indi-
cation, to be taken once daily on an
empty stomach at least one hour before
a meal. When taken at bedtime, it
reduces nocturnal gastric acidity to an
extent that has not been observed with
once-daily dosing of delayed-release
PPIs.
Dosage modification is generally not
needed in elderly patients or in those
with mild-to-moderate renal or hepatic
impairment.
The IR formulation is currently avail-
able as a peach-mint flavored powder for
oral suspension in 40- and 20-mg packets.
Because of this product’s unique phar-
macokinetic profile, there are no thera-
peutic equivalents, and it is not AB-rated
compared with delayed-release omepra-
zole (Prilosec®, Prilosec® OTC).50
The oral suspension offers an alterna-
tive for patients (e.g., elderly people and
children) who require PPI therapy for
acid-related conditions but who have dif-
ficulty swallowing tablets or capsules.
Absorption is optimized when patients
take this product on an empty stomach at
least one hour before a meal. For the
control of nighttime gastric acidity, how-
ever, the effect is greatest when it is
taken at bedtime on an empty stomach.
Patients should be instructed to pour
a packet of the powder for oral suspen-
sion into a small cup containing one to
two tablespoons (15–30 ml) of water, to
stir well, and to drink immediately. No
other liquids or foods should be mixed
with the powder. The cup should be
refilled with an additional small amount
of water, and this should also be con-
sumed right away to ensure that a com-
plete dose is ingested.35
For patients with nasogastric or oro-
gastric tubes, the powder should be con-
stituted with approximately 15 to 30 ml of
water (0.5–1.0 fluid ounce). Other liquids
or foods should not be used. The sus-
pension should be stirred well and ad-
ministered immediately, and a syringe
of the appropriate size should be used to
instill the suspension in the tube. The
suspension should be washed through
the tube with an additional 20 ml of
water.35
The FDA is currently reviewing
40-mg and 20-mg IR-OME capsules and
IR-OME chewable tablets.
CONCLUSION
The unique “non-enteric” formulation
of IR-OME provides more rapid absorp-
tion and decreased time to peak plasma
concentrations than do enteric-coated,
delayed-release PPIs. These pharmaco-
kinetic properties may confer advantages
for patients with acid-related disorders,
as suggested by emerging data about the
product’s effectiveness in controlling
nocturnal gastric pH in symptomatic
GERD patients and its ability to control
gastric acidity in critically ill patients.
Oral IR-OME, when taken on an empty
stomach at bedtime, is effective in con-
trolling nocturnal gastric acidity. It is an
alternative to the use of IV acid-
suppressant therapy for attaining and
sustaining a gastric pH above 6 and for
lowering the risk of upper GI bleeding in
critically ill patients.
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