DRUG REVIEW

Intravenous Proton Pump

Inhibitors
Danial E. Baker, PharmD, FASCP, FASHP
College of Pharmacy, Washington State University, Spokane, WA

Intravenous (IV) administration of a proton pump inhibitor (PPI) is a faster

way to achieve gastric acid suppression than oral administration of the same
agent. Peak suppression after IV administration occurs within hours, com-
pared with several days later after oral administration. Thus the IV route of
administration offers a faster onset of gastric suppression, achievement of
intragastric pH closer to neutrality, and better bioavailability. The PPIs that
have IV formulations in the United States (esomeprazole, lansoprazole, and
pantoprazole) are approved for different indications; the key differences
among them relate to their ability to reach specific gastric pH, time to
maintain a specific gastric pH, and ease of use of the IV formulation
(eg, reconstitution, requirement of inline filters, infusion times).
[Rev Gastroenterol Disord. 2006;6(1):22-34]

© 2006 MedReviews, LLC

Key words: Proton pump inhibitors • Esomeprazole • Lansoprazole • Pantoprazole •

Intravenous administration • Pharmacology • Gastroesophageal reflux disease

W
hen proton pump inhibitors (PPIs) were first introduced to the market,
they were only available as an oral capsule formulation. Since that
time, oral tablets, disintegrating tablets, suspensions, and intravenous
(IV) formulations have been developed (Table 1) to meet various administration
needs (eg, acute care, difficulty swallowing capsules or tablets, and pediatric and
geriatric patients). The IV formulations were developed for use in patients who
cannot take oral medications (eg, nothing by mouth, frequent emesis) or during

22 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS

 Intravenous PPIs

Table 1
Proton Pump Inhibitors Available in the United States and Their Dosage Forms

Agent Brand Name (Manufacturer) Dosage Forms

Esomeprazole Nexium® (AstraZeneca, Wilmington, DE) Delayed-release capsules: 20 mg, 40 mg
Nexium® IV (AstraZeneca) Injection: 20-mg and 40-mg single-dose vial
Lansoprazole Prevacid® (TAP Pharmaceuticals, Lake Forest, IL) Delayed-release capsules: 15 mg, 30 mg
Prevacid® (TAP Pharmaceuticals) Delayed-release oral suspension: 15-mg, 30-mg packets
Prevacid® (TAP Pharmaceuticals) SoluTab delayed-release orally disintegrating tablets:
15 mg, 30 mg
Prevacid® IV (TAP Pharmaceuticals) Injection: 30-mg single-dose vial
Pantoprazole Protonix® (Wyeth Pharmaceuticals, Madison, NJ) Delayed-release tablets: 20 mg, 40 mg
Protonix® IV (Wyeth) Injection: 40-mg single-dose vial
Omeprazole Prilosec® OTC (Procter and Gamble, Cincinnati, OH) Delayed-release tablets: 20 mg
Generics (Various) Delayed-release capsules: 10 mg, 20 mg, 40 mg
Prilosec® (AstraZeneca)
Zegerid® (Santarus, San Diego, CA) Powder for oral suspension: 20 mg, 40 mg
Rabeprazole Aciphex® (Eisai, Teaneck, NJ) Delayed-release tablets: 20 mg
Data from AstraZeneca, Wyeth Pharmaceuticals, TAP Pharmaceuticals, and Wolters Kluwer Health.44
14 15 18

critical illness.1-11 This article will becomes the active moiety that can IV administration was associated with
focus on comparing the PPIs that bind to cysteine residues within the a twofold higher peak concentration
have IV formulations in the United (H
/K
)-adenosine triphosphatase and a 66% to 83% greater area under
States: esomeprazole, lansoprazole, (ATPase) enzyme, resulting in inhibi- the plasma concentration–time curve
and pantoprazole. tion of gastric acid secretion.4,5,9,10,14 compared with oral administration of
The exception to this binding is pan- the same single dose. Differences were
Clinical Pharmacology toprazole, which forms a covalent similar but slightly less pronounced
All of the PPIs are prodrugs and re- bond to 2 sites (cysteine residue 813 after repeated daily administration for
quire acidic activation to be effective. and 822) of the H
, K
-ATPase en- 5 days.16 Comparative pharmacoki-
The oral formulations of PPIs are all zyme system.5,15 netics after IV and oral administration
acid labile and need to be protected The IV formulation improves the of 20 mg and 40 mg doses are
from premature activation. So the systemic bioavailability of PPIs be- summarized in Table 2. The bioavail-
drug is usually protected by the use of cause the acidity of the stomach and ability of oral esomeprazole is
an enteric coat around the tablets or
by filling the capsules with enteric-
coated granules.4,12,13 When the un- The bioavailability of oral esomeprazole is approximately 78% of that of
protonated prodrug is released in the IV esomeprazole.
small intestine, it is rapidly absorbed.
Once the orally administered PPI is
absorbed, it is activated and handled the upper duodenum and drug lability approximately 78% of that of IV
just like the intravenously adminis- in this environment are avoided. Thus esomeprazole.16 Esomeprazole is 97%
tered PPI. To be activated, the PPI more drug is delivered to the site of plasma protein bound. The apparent
must penetrate the cell membrane and action during the first few days of volume of distribution at steady-state
enter into the parietal cell. The PPI is therapy.4,5 is approximately 16 L.14
then transported across the canalicu- Esomeprazole is eliminated pri-
lar membrane into the canalicular Pharmacokinetics marily by hepatic metabolism by
space, where it is protonated and Esomeprazole cytochrome P450 (CYP)2C19 and
thereby trapped in the secretory In studies comparing the oral and CYP3A4.17 The metabolites of eso-
canaliculus of the parietal cell and IV administration of esomeprazole, meprazole are inactive.14 Less than

VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 23

Intravenous PPIs continued

15.7 L, with distribution primarily

Table 2 into the extracellular fluid.18 Lanso-
Comparative Pharmacokinetics of Intravenous and Oral Esomeprazole prazole is 97% plasma protein
bound.18
20 mg 40 mg Lansoprazole is extensively metab-
Intravenous Oral Intravenous Oral olized in the liver, primarily to 2
metabolites with little to no antisecre-
Cmax day 1 (mol/L) 3.32 0.78 6.77 2.97
tory activity.18 After oral administra-
Cmax day 5 (mol/L) 3.86 1.57 7.51 4.6 tion, no unchanged lansoprazole was
AUC day 1 (mol/h/L) 3.4 1.86 9.88 5.94 excreted in the urine. The metabolites
AUC day 5 (mol/h/L) 5.11 3.92 16.21 12.55 seem to be primarily eliminated in
T1⁄2 (h) 1.05 1.12 1.41 1.38 the bile.
Cmax, peak concentration; AUC, area under the plasma concentration–time curve;
The pharmacokinetics of 30 mg IV
T1⁄2, half-life. Data from Wilder-Smith CH et al.16 and oral lansoprazole doses are com-
pared in Table 3.19,20
Gender differences in lansoprazole
1% of the dose is excreted unchanged hepatic function. In patients with pharmacokinetics have not been ob-
in the urine.14 severe hepatic impairment (Child- served.18 Lansoprazole clearance is
The same recommendations for Pugh Class C), a dose of 20 mg once reduced, and the elimination half-life
dosage adjustments in special popula- daily should not be exceeded.14 increased (50%–100%) in elderly
tions are suggested for IV esomepra- subjects; however, dosage adjust-
zole as for oral esomeprazole. With Lansoprazole ments are not necessary because
oral esomeprazole, the area under the Peak plasma concentrations of lanso- accumulation does not occur due to
curve and peak concentration were prazole occur after the completion of the short half-life (1.9–2.9 hours).18
increased slightly in the elderly; how- a 30-minute IV infusion. The mean The pharmacokinetics of IV lansopra-
ever, dosage adjustments based on (SD) peak plasma concentrations zole have not been assessed in pedi-
age are not necessary.14 The pharma- after an IV infusion of lansoprazole atric patients.18
cokinetics of oral and IV esomepra- 30 mg was 1705  292 ng/mL. The In patients with chronic hepatic
zole have not been studied in patients mean area under the plasma concen- disease, the mean plasma half-life of
younger than 18 years.14 The area tration–time curve was 3192  1745 lansoprazole was prolonged from
under the curve and peak concentra- ng/h/mL.18 1.5 hours to 3.2 to 7.2 hours after oral
tion of esomeprazole were slightly The apparent volume of distribu- administration. An increase in mean
increased in women compared with tion of lansoprazole is approximately area under the curve up to 500% was
men with both oral and IV adminis-
tration; however, dosage adjustment
Table 3
based on gender is not necessary.14
Comparative Pharmacokinetics of Lansoprazole 30 mg
Because less than 1% of the es-
omeprazole dose is eliminated un- Administered Orally and Intravenously
changed in the urine, renal impair-
ment is not expected to significantly Intravenous Oral
affect the pharmacokinetics of (n  64) (n  62)
esomeprazole.14 Bioavailability (%)  80
The pharmacokinetics of oral Tmax* (h) 0.5† 1.5–1.8
esomeprazole was not altered in
Cmax (ng/mL)* 1652–1884 807–1052
patients with mild to moderate he-
patic impairment (Child-Pugh Classes AUC24* (ng/h/mL) 3192–3611 2422–3101
A and B). In patients with severe T1⁄2* (h) 1.13–1.3 1.1–1.24
hepatic insufficiency (Child-Pugh Tmax, time to peak concentration; Cmax, peak concentration; AUC, area under the plasma concentra-
Class C), the area under the curve of tion–time curve; T1⁄2, half-life. Data from Freston FW et al,19,20 and TAP Pharmaceuticals.18
*Range of means from 2 studies and multiple time points.
esomeprazole was two- to threefold †
At completion of the 30-minute infusion.
higher than in subjects with normal

24 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS

 Intravenous PPIs

observed at steady-state in patients zole is increased to 3.5 to 10 hours. 40 mg. The dose was infused intra-
with hepatic impairment. Dosage Accumulation remains minimal venously over 30 minutes. The per-
reductions should be considered in ( 23%) with once-daily dosing in centage of time the gastric pH was
patients with severe hepatic disease.18 this population.12,15 Pantoprazole also greater than 4 on day 5 was 49.5%
In patients with severe renal insuf- undergoes metabolism to a minor (95% confidence interval, [CI] 41.9%-
ficiency, lansoprazole protein bind- extent by CYPs 3A4, 2D6, and 2C9.12 57.2%) with esomeprazole 20 mg and
ing, half-life, and total area under the Approximately 71% of the dose is 66.2% (95% CI, 62.4%-70.0%) with
curve are reduced, whereas peak excreted in the urine as metabolites, esomeprazole 40 mg.14
concentration and time to peak con- with another 18% of the dose ex- Mean intragastric pH over a
centration are unchanged. No adjust- creted in the feces through biliary 24-hour period was comparable after
ments in dose are necessary because excretion. No unchanged drug is administration of oral and IV lanso-
of these changes.18 excreted in the urine.12,15 prazole 30 mg in a crossover study.
Liver dysfunction can decrease the Compared with oral lansoprazole, IV
Pantoprazole clearance of pantoprazole to an ex- lansoprazole produced a greater in-
IV pantoprazole is given as a tent similar to that observed in slow tragastric pH within the first hour of
15-minute infusion. The serum con- metabolizers. In patients with severe administration, both on the first day
of administration and on day 5.19,22
Oral and IV lansoprazole 30-mg doses
In patients with severe hepatic dysfunction, the potential for drug accumula- produced comparable reductions in
tion ( 21%) with pantoprazole once-daily dosing must be weighed against basal and maximal acid output in
the potential for reduced acid control with administration every other day. another study, although IV adminis-
tration was associated with a greater
first-dose effect and less first-dose
centration time curve increases cirrhosis, the elimination half-life is variability.19,23 With once-daily oral
proportionally to the IV doses from increased to 7 to 9 hours.12,15 Dosage administration, the intragastric pH
10 mg to 80 mg. Peak serum concen- adjustments are not necessary in pa- was lower during the second 12 hours
trations occur at the end of the IV in- tients with mild to moderate hepatic of the dosing interval, and intragas-
fusion and are 5.52 g/mL after a 40- dysfunction.12,15 In patients with tric pH was increased for a greater
mg dose.15 After a single 40-mg IV severe hepatic dysfunction, the poten- period of time with twice-daily
dose administered over 15 minutes, tial for drug accumulation ( 21%) IV lansoprazole.24-26 Comparable in-
plasma concentrations at the end of with once-daily dosing must be tragastric pH changes were observed
the infusion ranged from 3.21 g/mL weighed against the potential for re- when lansoprazole 30 mg was admin-
to 7.05 g/mL in 12 healthy subjects. duced acid control with administra- istered intravenously over 2 minutes
The mean half-life was 1.9 hours.21 tion every other day.12,15 Severe renal or over 2 hours.25
The total clearance of pantoprazole
is 7.6 L/h to 14 L/h, and its apparent
volume of distribution is 11 L to 23.6 L. Compared with oral lansoprazole, IV lansoprazole produced a greater intra-
Serum protein binding is 98%, pri- gastric pH within the first hour of administration.
marily to albumin.
Pantoprazole is extensively metab-
olized in the liver through the CYP impairment and hemodialysis have no Acid-suppressing activity is appar-
system after both oral and IV admin- impact on the clearance of pantopra- ent within 15 to 20 minutes of IV
istration.12,15 Lansoprazole, omepra- zole.12,15 Dosage adjustments are not pantoprazole administration.27 Acid
zole, pantoprazole, and rabeprazole needed in patients with renal dys- suppression is maintained for at least
are metabolized by the CYP2C19 function or in the elderly.12,15 24 hours after a single IV dose.27
enzyme system. In subjects with Maintenance of a specific pH can be
CYP2C19 deficiency (eg, 3% of Cau- Pharmacodynamics: Influence achieved with a loading dose of pan-
casians and African Americans and on Intragastric pH toprazole followed by a continuous
17%–23% of Asians) due to genetic Mean intragastric pH over a 24-hour infusion. The administration of pan-
polymorphism (slow metabolizers), period was determined after 5 days of toprazole 80 mg intravenously, fol-
the elimination half-life of pantopra- once daily esomeprazole 20 mg or lowed by 8 mg/h, produced a pH

VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 25

Intravenous PPIs continued

sion of basal acid output and maxi-

Table 4 mal acid output. Symptomatic im-
FDA-Approved Indications for the Injectable Proton Pump Inhibitors provement was not assessed.14
The combined results of 2 studies
Indication Esomeprazole Lansoprazole Pantoprazole comparing the effects of oral and
Short-term treatment (up to 7 d) X IV esomeprazole on intragastric pH
of all grades of erosive esophagitis have been reported. In an open-label,
in patients unable to take oral randomized, crossover study con-
therapy ducted in Switzerland, the effects of
Short-term treatment (up to 10 d) X X oral esomeprazole 20 mg and IV
of gastroesophageal reflux disease esomeprazole 20 mg were compared
associated with a history in 24 healthy subjects. In the
of erosive esophagitis in patients other, double-dummy, randomized,
for whom oral therapy is not possible crossover study conducted in Sweden,
or appropriate
the effects of oral esomeprazole
Treatment of pathologic X 40 mg and IV esomeprazole 40 mg
hypersecretory conditions associated were compared in 40 healthy subjects.
with Zollinger-Ellison syndrome
Subjects received esomeprazole as a
or other neoplastic conditions
30-minute infusion once daily for
FDA, US Food and Drug Administration. Data from AstraZeneca,14 Wyeth Pharmaceuticals,15 and 5 days or orally once daily for 5 days,
TAP Pharmaceuticals.18
followed by a 13-day washout period,
and then administration of the alter-
greater than 3 in 99%, pH greater they all are probably effective in the nate agent for 5 days. Continuous
than 4 in 99%, pH greater than 5 in treatment of these medical conditions. 24-hour intragastric pH monitoring
94%, and pH greater than 6 in 84% in Table 4 compares the FDA-approved was conducted at baseline and on
healthy volunteers.28 indications for the available in- days 1 and 5 of drug administration.
Thirty-three healthy patients were jectable PPIs. In both studies, acid suppression and
given nasogastric lansoprazole or IV pharmacokinetics were compared
pantoprazole to determine the impact Clinical Efficacy after day 1 and day 5 of daily dosing.
of these agents on 24-hour intragas- Esomeprazole On day 1, the time spent with an in-
tric pH. Patients were given 5 days of The IV esomeprazole prescribing tragastric pH greater than 4 was
lansoprazole 30 mg or pantoprazole information contains information slightly greater with the 40-mg
40 mg once daily, then were switched on 4 multicenter, open-label, IV dose (10.1 hours) compared with
to the other agent for another 5 days. crossover studies comparing IV and the 40-mg oral dose (8.8 hours,
pH evaluations were done on days 1 oral esomeprazole in patients with difference 1.3 hours; 95% CI, 0.3-
and 5 of each therapy. The mean 24- symptoms of gastroesophageal reflux 2.4 hours). No differences were ob-
hour pH was 3.05 on day 1 with lan- disease (GERD), with or without served in the amount of time spent
soprazole and 2.76 with pantopra- erosive esophagitis. A total of 206 with intragastric pH greater than 4
zole. These values changed to 3.65 patients (aged 18–72 years; 112 between the oral and IV routes on ei-
and 3.45 after 5 days of therapy. The female; 110 Caucasian, 50 African ther days at the 20-mg dose and on
percentage of time the pH was American, 10 Asian, and 36 other day 5 with the 40-mg dose. At the 20-
greater than 4 was 26.6% on day 1 race) were randomized to receive IV mg dose, the amount of time with in-
with lansoprazole and 18.96% with or oral esomeprazole 20 mg or 40 mg tragastric pH greater than 4 was
pantoprazole. These values changed once daily for 10 days, and then were 7.3 hours with IV administration and
to 40.48% and 36.55% after 5 days switched to the alternate route of 6.6 hours with oral administration on
of therapy.29 therapy for 10 days at the same dose. day 1, and 11.9 hours with IV admin-
The IV formulation was administered istration and 12.3 hours with oral
Indications as a 3-minute injection in 2 studies administration on day 5. At the
The US Food and Drug Administra- and as a 15-minute infusion in the 40-mg dose, the amount of time with
tion (FDA)-approved indications are other 2 studies. The IV and oral for- intragastric pH greater than 4 was
different for the IV PPIs; however, mulations produced similar suppres- 15.9 hours with IV administration and

26 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS

 Intravenous PPIs

15.3 hours with oral administration toprazole (P  .001) over the first
on day 5.16 24 hours and was 4.3 with esomepra-
Oral and IV esomeprazole 40 mg Esomeprazole 40 mg IV
zole and 3.2 with pantoprazole
20 Pantoprazole 40 mg IV
have also been compared in a ran- (P  .0001) on day 5. Overall, eso-
domized, double-blind study includ- P  .0001 meprazole was associated with faster
ing 246 patients with erosive 15 and greater intragastric acid control
13.9
esophagitis at 10 sites in South Africa. than pantoprazole at the 40-mg dose.32

Hours
During the first week of therapy,
P  .001
patients received esomeprazole 40 mg 10 9 Lansoprazole
once daily orally or as a 3-minute 8.3
A multicenter, double-blind, placebo-
IV injection or 30-minute IV infusion. controlled study enrolled 87 patients
5.3
All patients then received oral es- 5 with erosive esophagitis. These
omeprazole 40 mg once daily for patients were treated with oral lanso-
3 weeks, with healing assessed at prazole 30 mg once daily for 7 days
week 4. Healing rates were compara- 0 and then switched to IV lansoprazole
ble regardless of the route of admin- Day 1 Day 5 30 mg or IV placebo (normal saline)
istration during the first week: 79.7% once daily for 7 days. Maximum and
(95% CI, 69.2%-88%) for the 3- Figure 1. Time with intragastric pH  4. Reprinted basal acid output were assessed
with permission from Wilder-Smith CH et al.32
minute injection group, 80.2% (95% 21 hours after the last oral and IV
CI, 69.9%-88.3%) for the 30-minute dose. The oral and IV formulations
infusion group, and 82.6% (95% CI, and 5 (Figure 1; day 1 P  .001, day produced comparable suppression of
72.9%-89.9%) for the oral group.30,31 5 P  .0001). During the first 4 hours maximum and basal acid output. The
Acid control with IV esomeprazole of dosing on day 1, an intragastric pH results of this efficacy study are sum-
and IV pantoprazole has been com- greater than 4 was achieved for marized in Table 5.18
pared in an open-label, randomized,
crossover study in 25 healthy volun-
teers. Subjects received esomeprazole Overall, esomeprazole was associated with faster and greater intragastric
40 mg or pantoprazole 40 mg as a acid control than pantoprazole at the 40-mg dose.
15-minute infusion once daily for
5 days, followed by a 13-day washout
period, and then administration of the 1.7 hours with esomeprazole, com- The effect of IV lansoprazole on
alternate agent for 5 days. Continu- pared with 0.6 hours with pantopra- gastric acid secretion in patients with
ous 24-hour intragastric pH monitor- zole (P  .0001). Median pH was 3.1 postoperative stress was assessed in
ing was conducted at baseline and on with esomeprazole and 2.3 with pan- an open-label study enrolling 82
days 1 and 5 of drug administration.
At baseline, the mean amount of time
over 24 hours that the intragastric pH
was greater than 4 was 2.6 hours Table 5
(95% CI, 1.3-4 hours), and the median Acid Output in Patients with Erosive Esophagitis After
pH was 1.6. Time with intragastric pH 7 Days of Lansoprazole or Placebo Therapy
greater than 4 was greater after es-
omeprazole than after pantoprazole Oral Intravenous Intravenous
during the first day and fifth day of Lansoprazole Lansoprazole Placebo
administration. The difference was
Median maximum acid output 7.16 7.64 26.90*
apparent within the first 4 hours of
(n  80) (n  56) (n  17)
administration of the first dose.
Median basal acid output 0.77 0.51 3.19†
Esomeprazole was associated with
(n  81) (n  55) (n  16)
8.3 hours and 13.9 hours with an in-
tragastric pH greater than 4 on days 1 Data from TAP Pharmaceuticals.18
*P  .001, intravenous lansoprazole vs placebo.
and 5, compared with 5.3 hours and †
P  .005, intravenous lansoprazole vs placebo.
9 hours for pantoprazole on days 1

VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 27

Intravenous PPIs continued

hospitalized patients ages 20 to Pantoprazole tients, respectively, with these symp-

75 years. Patients received lansopra- Oral and IV pantoprazole are equally toms at baseline. Marked improve-
zole 15 mg twice daily (n  41) or effective in suppressing gastric acid ment in key symptoms was reported
lansoprazole 30 mg twice daily (n  output and providing symptomatic after the third day of IV pantoprazole
41) for 3 days after surgery under control in patients with GERD.34-39 therapy.36
general anesthesia for gastrointestinal Pantoprazole is also effective in de- In a similar open-label study, pan-
disease. Intragastric pH was assessed creasing antacid use and decreasing toprazole was administered intra-
every 8 hours. For patients with pre- acid output in patients with sympto- venously for 5 to 7 days, followed by
treatment intragastric pH less than 3, matic esophagitis and GERD.35,39,40 oral administration for up to 7 weeks
responses were defined as excellent, Efficacy of pantoprazole in control- in 176 patients with reflux esophagi-
good, fair, or poor. For patients with ling GERD symptoms was assessed in tis (stage II or III, Savary-Miller clas-
pretreatment intragastric pH above 3, a study enrolling 63 patients with sification). The safety and efficacy of
responses were defined as excellent, GERD who were randomly assigned pantoprazole therapy was assessed in
good, fair, or poor. Efficacy was ex- therapy with pantoprazole 20 mg or 142 patients who completed the
cellent in 20 (52.6%) of 38 assessable 40 mg orally for 10 to 14 days and study. Healing was achieved in 114 of
patients treated with lansoprazole then were switched to IV pantopra- 142 patients (80%) at week 4 and 132
15 mg and 22 (59.5%) of 37 assess- zole 20 mg or 40 mg or placebo for of 142 patients (93%) at week 8. After
able patients treated with lansopra- 7 days. Patients switched to either 2 weeks, heartburn, acid regurgita-
zole 30 mg. An additional 5 patients dose of IV pantoprazole used less tion, and pain on swallowing resolved
in the 15-mg group and 6 in the 30- antacid than those patients switched in 87%, 90%, and 93% of patients,
mg group achieved a good response, to placebo. No difference in antacid respectively. The reflux symptom
for an overall assessment of excellent use was observed with the pantopra- score was improved within 4 days of
or good in 65.8% in the 15-mg group zole oral and IV groups or between initiating IV pantoprazole.37
and 75.7% in the 30-mg group.33 the 20-mg and 40-mg doses. Antacid IV pantoprazole has also been as-
IV lansoprazole has been assessed was used by 23.3% of patients during sessed in an observational study con-
in an open-label pilot study enrolling therapy with oral pantoprazole ducted in hospitalized patients in 17
47 patients with upper gastrointesti- 40 mg, compared with 21.8% of pa- hospitals in Germany.41 Pantoprazole
nal bleeding due to gastric or duode- tients switched to IV pantoprazole was administered to 269 patients
nal ulcers. Patients received IV lanso-
prazole 15 mg twice daily (n  26) or
30 mg twice daily (n  20) for 7 days. Oral and IV pantoprazole are equally effective in suppressing gastric acid
The hemostatic effects, determined by output and providing symptomatic control in patients with gastroesophageal
gastric probe or endoscope, were reflux disease.
rated excellent (if bleeding was
stopped within 36 hours), good (if
bleeding was stopped within and 57.1% of patients switched to with gastric ulcer (28%), duodenal
72 hours), fair (if bleeding was placebo.35 ulcer (23%), reflux esophagitis (23%),
stopped within 7 days), or poor (if Pantoprazole 40 mg once daily or other gastroduodenal disease. Di-
bleeding was not stopped within administered intravenously for 5 to agnosis was confirmed by endoscopy
7 days or treatment was changed). 7 days, followed by oral administra- in 91% of patients. Institution of ther-
Hemostasis was rated excellent in 14 tion for up to 8 weeks, has been as- apy was at the physician’s discretion.
(63.6%) of 22 patients treated with sessed in 110 patients with moderate The usual pantoprazole dosage was
lansoprazole 15 mg and 13 (72.2%) of or severe GERD (stage II or III, 40 mg once daily infused in the
18 patients treated with lansoprazole Savary-Miller classification). Com- morning over 2 to 15 minutes. In el-
30 mg. An additional 4 patients in the plete healing in the intention-to-treat derly patients and those with renal
15-mg group and 3 patients in the group occurred in 85 of 110 patients impairment, a maximum daily dose of
30-mg group achieved a response (77%) at 4 weeks and 93 of 110 pa- 40 mg was recommended. In patients
rated good, for an overall assessment tients (85%) at 8 weeks. After with severe hepatic dysfunction, a
of excellent or good in 81.8% in the 2 weeks, heartburn, acid regurgita- maximum daily dose of 20 mg was
15-mg group and 88.9% in the 30-mg tion, and pain on swallowing re- recommended. Pantoprazole was
group.26 solved in 97%, 98%, and 100% of pa- administered in 0.9% sodium chloride

28 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS

 Intravenous PPIs

solution in 99% of cases. It was 10 days of observation. The study was twice daily did not respond to panto-
administered peripherally in 82% of completed per protocol by 61 patients prazole therapy at 80 mg or 120 mg
patients and centrally in 18%. The in the pantoprazole group and 58 pa- twice daily (AO  12.7 mEq/h on day
40-mg dose was administered to tients in the ranitidine group. The rate 7, from a baseline AO of 0.65 mEq/h
94.7% of patients, whereas 5% re- of rebleed after 48 hours of therapy with oral omeprazole).43
ceived 20 mg, and 0.3% received was 10% in both groups, and the mor-
80 mg. The mean duration of IV pan- tality rate after 10 days was 1.5% in Contraindications
toprazole therapy was 6 days; 90% of both groups.42 Use of any of the injectable PPIs is
patients received IV pantoprazole for The efficacy of pantoprazole IV contraindicated in patients with
no more than 10 days. An orally ad- after oral PPI therapy has been as- known hypersensitivity to the drug
ministered acid inhibitor was contin- sessed in 14 patients with Zollinger- and any of the formulation ingredi-
ued in 84% of patients during their Ellison syndrome.43 Before the switch ents (see Table 6).
hospitalization and in 72% of patients to IV pantoprazole, 9 patients were
after discharge. Concomitant illness taking oral omeprazole (3, 20 mg once Warnings and Precautions
was present in 214 patients (80%), pri- daily; 3, 20 mg twice daily; and 1 Treatment with any of these IV for-
marily circulatory (23%), digestive each, 40, 60, or 100 mg twice daily), mulations should be discontinued as
(17%), or endocrine, nutritional, or and 5 patients were taking oral lanso- soon as the patient is able to resume
metabolic (17%). Improvement was prazole (2 each, 30 mg once daily or treatment with an oral PPI.14,15,18
observed in 241 patients (90%). At as- twice daily; and 1, 60 mg twice daily). Symptomatic response to therapy
sessment after the last pantoprazole Acid secretion was controlled in all with any PPI does not preclude the
infusion, complete healing was re- patients taking oral PPI therapy, with presence of gastric malignancy.14,15,18
ported for 7.3% of patients, significant a mean acid output of 0.55 mEq/h. Pa- The safety and effectiveness of any
improvement was reported for 70.2% tients were then switched to IV panto- of these PPIs has not been established
of patients, and slight improvement prazole 80 mg twice daily for 7 days, in pediatric patients.14,15,18
was reported for 14.5% of patients. with the dose titrated upward to a
Physicians judged the efficacy of the maximum of 240 mg/24 hours if acid Esomeprazole
IV pantoprazole therapy as “very output was not controlled. Acid output Esomeprazole is classified as Preg-
good” or “good” in 89% of patients. (AO) was controlled (AO  10 mEq/h nancy Category B. Esomeprazole
Tolerability was assessed to be “very or  5 mEq/h after gastric acid– should be used during pregnancy
good” or “good” in 98% of patients.41 reducing surgery) in 13 of 14 patients only if clearly needed.14
IV pantoprazole has been compared (93%) at the 80-mg dose administered Esomeprazole excretion in milk
with IV ranitidine in the prevention of twice daily. One patient previously has not been assessed; however,
peptic ulcer rebleeding in 133 pa- treated with oral omeprazole 100 mg omeprazole concentrations have
tients.42 The initial bleeding was con-
trolled with endoscopic homeostasis.
Patients were then randomized to
treatment with pantoprazole or raniti- Table 6
dine, and the study medication was Chemical Classification and Product Ingredients of the
given within 1 hour of the endoscopic
Intravenous Proton Pump Inhibitors
homeostasis. The pantoprazole was
given as a 40-mg IV dose and then
followed by an 8-mg/h continuous Esomeprazole Lansoprazole Pantoprazole
infusion for 2 days. The ranitidine Chemical classification
was given as a 50-mg IV dose and Benzimidazole X X X
then followed by a 12.5-mg/h contin- Product ingredients
uous infusion for 2 days. Endoscopic Edetate disodium X X
examination was repeated 48 hours Mannitol X
after the initial endoscopic procedure Meglumine X
or on suspicion of rebleeding. Follow- Sodium hydroxide X X X
up on the patient’s status was contin- 14 15
Data from AstraZeneca, Wyeth Pharmaceuticals, and TAP Pharmaceuticals.18

ued for 8 more days, for a total of

VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 29

Intravenous PPIs continued

been measured in breast milk after list of the adverse events reported with increased diazepam plasma levels.
omeprazole therapy. Discontinuation pantoprazole can be found in the oral This drug interaction is not believed
of nursing or esomeprazole is recom- and IV product labeling. to be clinically important.14
mended in breast-feeding mothers Reactions specific to the IV route The pharmacokinetics of esomepra-
due to the potential risks of adverse have included mild itching at the in- zole were not altered by concomitant
effects.14 jection site and mild focal erythema administration of diazepam, pheny-
at the IV insertion site. The incidence toin, oral contraceptives, or quini-
Lansoprazole and nature of adverse events did not dine.14 Concomitant administration
Lansoprazole is classified in Preg- seem to differ between oral and IV with naproxen or rofecoxib did not
nancy Category B. Lansoprazole administration. result in changes in the pharmacoki-
should be used during pregnancy netics of esomeprazole or either of
only if clearly needed.18 Drug Interactions the nonsteroidal anti-inflammatory
Lansoprazole or its metabolites are Changes in pH might influence the drugs.14
excreted in the milk of rats. It is not absorption of some drugs from the
known whether lansoprazole is ex- stomach. PPIs might decrease the ab- Lansoprazole
creted in human milk. Owing to the sorption of ketoconazole, ampicillin Lansoprazole is a CYP3A and
potential for adverse effects in the in- esters, and iron salts and increase the CYP2C19 substrate. Interactions have
not been observed between lansopra-
zole and warfarin, diazepam, pheny-
The incidence and nature of adverse effects of these 3 PPIs did not seem to toin, propranolol, antipyrine, in-
differ between oral and IV administration. domethacin, ibuprofen, prednisone, or
clarithromycin in healthy subjects.
Administration of lansoprazole with
fant, use in nursing mothers is not absorption of benzyl penicillin by theophylline resulted in a small (10%)
recommended.18 raising the pH of the stomach.14,15,18 increase in theophylline clearance.
The dose of theophylline might need
Pantoprazole Esomeprazole to be adjusted when lansoprazole
Pantoprazole is classified in Preg- Esomeprazole is extensively metabo- therapy is initiated or discontinued.18
nancy Category B. Controlled studies lized in the liver by CYP2C19 and Although neither a pharmacoki-
in pregnant women are lacking.15 CYP3A4.14 netic or pharmacodynamic interac-
Pantoprazole and its metabolites Esomeprazole is not likely to inhibit tion was observed between lansopra-
are excreted in the milk of rats. It is CYPs 1A2, 2A6, 2C9, 2D6, 2E1, or zole and warfarin in healthy subjects,
unknown whether pantoprazole is 3A4. Drug interactions are not antici- cases of increased INR and prothrom-
excreted in human breast milk, but pated with substrates of these en- bin time have been reported in
the manufacturer recommends that zymes. Drug interaction studies have patients receiving PPIs, including
either nursing or the drug be shown that esomeprazole does not lansoprazole and warfarin concomi-
discontinued.15 have any clinically important interac- tantly. INR or prothrombin time mon-
No changes in cortisol, testosterone, tions with phenytoin, warfarin, quini- itoring is recommended in patients
triiodothyronine, thyroxine, thyroid- dine, clarithromycin, or amoxicillin. receiving lansoprazole and warfarin
stimulating hormone, thyronine-bind- However, postmarketing reports have concomitantly.18
ing protein, parathyroid hormone, in- described increases in international
sulin, glucagon, renin, aldosterone, normalized ratio (INR) and prothrom- Pantoprazole
follicle-stimulating hormone, luteiniz- bin time in patients receiving con- Pantoprazole does not seem to affect
ing hormone, prolactin and growth comitant esomeprazole and warfarin. the metabolism of other medications.
hormone have been reported.15 Monitoring is recommended in pa- Nor is the metabolism of pantoprazole
tients receiving this combination.14 affected by other medications.15
Adverse Reactions Esomeprazole might interfere with
All 3 of these PPIs are well tolerated.14 CYP2C19. Administration of eso- Dosing
Common adverse events included meprazole 30 mg with diazepam, a Esomeprazole
headache, flatulence, nausea, dyspep- CYP2C19 substrate, resulted in a 45% The recommended dose of injectable
sia, and abdominal pain. A complete reduction in diazepam clearance and esomeprazole is 20 mg or 40 mg once

30 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS

 Intravenous PPIs

daily by IV injection (no less than Pantoprazole Product Availability

3 minutes) or IV infusion (10 to The recommended adult dose of IV Esomeprazole
30 minutes).14 Esomeprazole should pantoprazole is 40 mg given once Esomeprazole is available as a sterile,
not be administered concomitantly daily by IV infusion for 7 to freeze-dried, porous cake or powder,
with any other medications through 10 days.15 in a 5-mL vial.14 It is intended for IV
the same line or tubing. The line The rate of the infusion should be administration after reconstitution
should always be flushed with either 7 mL/min and last approximately with 0.9% Sodium Chloride Injection
0.9% Sodium Chloride Injection USP, 15 minutes.15 The pantoprazole should USP, Lactated Ringer’s Injection USP,
Lactated Ringer’s Injection USP, or be given through a dedicated IV line or 5% Dextrose Injection USP. Avail-
5% Dextrose Injection USP before and or through a Y-site.15 The infusion line able vials contain esomeprazole
after administration of the esomepra- should be flushed before and after sodium 21.3 mg or 42.5 mg, equiva-
zole.14 pantoprazole administration with ei- lent to esomeprazole 20 mg or 40 mg,
A dose of 20 mg should not be ex- ther 5% Dextrose Injection USP, 0.9% edetate disodium 1.5 mg, and sodium
ceeded in patients with severe hepatic Sodium Chloride Injection USP, or hydroxide as needed for pH adjust-
impairment (Child-Pugh Class C). No Lactated Ringer’s Injection USP.15 ment. The stability of the reconsti-
dosage adjustments are necessary in Pantoprazole is incompatible with mi- tuted solution is pH dependent, with
the elderly, patients with renal dys- dazolam and might be incompatible the rate of degradation increasing
function, or on the basis of gender.14 with products containing zinc.15 with decreasing pH.14
Dosage adjustments are not neces-
Lansoprazole sary in the elderly, patients with renal Lansoprazole
The recommended dose is 30 mg once insufficiency, and patients with mild Lansoprazole is available as a
daily for up to 7 days, administered or moderate hepatic impairment. In lyophilized powder in vials contain-
intravenously over 30 minutes in patients with severe hepatic impair- ing lansoprazole 30 mg, mannitol
50 mL 0.9% Sodium Chloride Injec- ment, the potential for drug accumu- 60 mg, meglumine 10 mg, and sodium
tion USP, Lactated Ringer’s Injection lation ( 21%) with once-daily dos- hydroxide 3.45 mg. Each pack con-
USP, or 5% Dextrose Injection USP. ing must be weighed against the tains one 30-mg single-dose vial and
Use of an in-line filter is required. A potential for reduced acid control one in-line filter (1.2-m pore size).18
dedicated line is not required; how- with administration every other day.15 Upon reconstitution with sterile
ever, the line should be flushed before The safety and effectiveness of water for injection, the solution has a
and after administration of lansopra- pantoprazole in pediatric patients pH of 11. The pH is approximately
zole. Lansoprazole injection should have not been established.15 10.2 after further dilution with 0.9%
not be administered with other drugs Table 7 summarizes the IV dose and Sodium Chloride for Injection USP, 10
or diluents.18 administration for esomeprazole, lan- after further dilution with Lactated
Lansoprazole for injection must be soprazole, and pantoprazole. Ringer’s Injection USP, and 9.5 after
reconstituted with 5 mL of Sterile It should be noted that many clini- dilution with 5% Dextrose Injection
Water for Injection USP, producing a cians use IV PPIs for the treatment of USP. The rate of degradation of the
solution containing lansoprazole ulcer bleeding. Although the only compound in aqueous solution in-
6 mg/mL (30 mg/5 mL). Use of other published clinical studies have re- creases with decreasing pH.18 The
diluents might result in precipitation ported on the use of omeprazole with reconstituted solution can be held
or the formation of particulates.18 The an 80-mg bolus followed by an for 1 hour when stored at 25C (77F)
reconstituted solution should be fur- 8 mg/h continuous infusion for this before further dilution.18
ther diluted in 50 mL 0.9% Sodium clinical indication, many have ex-
Chloride Injection USP, Lactated trapolated this to pantoprazole, lanso- Pantoprazole
Ringer’s Injection USP, or 5% Dex- prazole, and esomeprazole, using an The IV formulation of pantoprazole is
trose Injection USP. Lansoprazole so- 80-mg, 60-mg, and 40-mg bolus, re- supplied as a freeze-dried powder in a
lution should be administered intra- spectively, followed by an 8-mg/h, 6- clear glass vial fitted with a rubber
venously with the supplied in-line mg/h, and 4-mg/h infusion of these stopper. Each vial contains pantopra-
filter. The filter must be used to re- agents. The effectiveness of these zole sodium (equivalent to pantopra-
move precipitate that might form doses are as yet unknown but again zole 40 mg).15
when the reconstituted drug is mixed have become widely used for this The dry powder in the pantoprazole
with IV solutions.18 indication. vial should be reconstituted with 10 mL

VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 31

Intravenous PPIs continued

Table 7
Intravenous Dose and Administration of Intravenous Proton Pump Inhibitors

Esomeprazole Lansoprazole Pantoprazole

Dose GERD/erosive esophagitis: Erosive esophagitis: GERD/erosive esophagitis:

20 mg or 40 mg qd for 30 mg qd for up to 7 d 40 mg qd for 7–10 d
up to 10 d Hypersecretory conditions:
80 mg every 12 h
Administration 3-min injection or 30-min infusion 2-min injection or
10- to 30-min infusion 15-min infusion
In-line filter No Yes No
required?
Reconstitution • 5 mL 0.9% Sodium 5 mL sterile water for 10 mL 0.9% Sodium
Chloride Injection USP for Injection USP Chloride Injection USP
3-min injection
• 5 mL 0.9% Sodium
Chloride Injection USP,
Lactated Ringer’s Injection
USP, or 5% Dextrose
Injection USP if undergo-
ing further dilution for
infusion
Dilution for infusion Dilute to 50 mL with 0.9% Dilute in 50 mL 0.9% Dilute to 100 mL with 5%
Sodium Chloride Injection Sodium Chloride Injection Dextrose Injection USP,
USP, Lactated Ringer’s USP, Lactated Ringer’s 0.9% Sodium Chloride
Injection USP, or 5% Injection USP, or 5% Injection USP, or Lactated
Dextrose Injection USP for Dextrose Injection USP for Ringer’s Injection USP for
the 10- to 30-min infusion. 30-min infusion. Administer 15-min infusion. The diluted
Administer within 12 h within 24 h when diluted solution should be
when diluted with 0.9% with 0.9% Sodium Chloride administered within 24 h
Sodium Chloride or Lactated or Lactated Ringer’s and
Ringer’s and within 6 h within 12 h when diluted
when diluted with 5% with 5% Dextrose
Dextrose
GERD, gastroesophageal reflux disease.
Data from AstraZeneca,14 Wyeth Pharmaceuticals,15 and TAP Pharmaceuticals.18

of 0.9% Sodium Chloride Injection, stored at room temperature but needs administration occurs within hours,
USP. Before administration this solu- to be used within 24 hours.15 compared with several days later after
tion should be diluted with 100 mL of The available dosage forms for eso- oral administration. Thus the IV route
5% Dextrose Injection USP, 0.9% meprazole, lansoprazole and panto- of administration offers a faster onset
Sodium Chloride Injection USP, or prazole are summarized in Table 8. of gastric suppression, achievement of
Lactated Ringer’s Injection USP. The intragastric pH closer to neutrality,
final concentration of the diluted so- Conclusion and better bioavailability. All of the
lution is approximately 0.4 mg/mL.15 IV administration of the PPI is a faster IV formulations are approved for dif-
The reconstituted solution can be way to achieve gastric acid suppres- ferent indications; the key differences
stored at room temperature for up to sion than oral administration of the between them relate to their ability to
6 hours. The final solution can be same agent. Peak suppression after IV reach specific gastric pH, time to

32 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS

 Intravenous PPIs

Table 8
Available Esomeprazole, Lansoprazole, and Pantoprazole Dosage Forms and Storage Recommendations

Agent Dosage Forms Storage*

Esomeprazole Delayed-release capsules: 20 mg, 40 mg Room temperature
Injection: 20-mg and 40-mg single-dose vial
Lansoprazole Delayed-release capsules: 15 mg, 30 mg Room temperature
Delayed-release oral suspension: 15-mg, 30-mg packets
SoluTab delayed-release orally disintegrating tablets: 15 mg, 30 mg
Injection: 30-mg single-dose vial
Pantoprazole Delayed-release tablets: 20 mg, 40 mg Room temperature
Injection: 40-mg single-dose vial
Data from AstraZeneca,14 Wyeth Pharmaceuticals,15 TAP Pharmaceuticals,18 and Wolters Kluwer Health.44
*USP controlled room temperature (20C–25C; 68F–77F); with excursions permitted to 15C–30C (59F–86F). Refrigerator 2C–8C (36F–46F).

maintain a specific gastric pH, and 3. Khuroo M, Khuroo MS, Farahat KLC, Kagevi IE. 7. Johnson DA. Alternative dosing for PPI therapy:
Treatment with proton pump inhibitors in acute rationale and options. Rev Gastroenterol Disord.
ease of use of the IV formulation (eg, non-variceal upper gastrointestinal bleeding: a 2003;3(suppl 4):S10-S15.
reconstitution, requirement of in-line meta-analysis. J Gastroenterol Hepatol. 2005; 8. Devlin JW. Proton pump inhibitors for acid
filters, infusion times). 20:11-25. suppression in the intensive care unit: formulary
4. Freston JW. Therapeutic choices in reflux disease: considerations. Am J Health Syst Pharm. 2005;
defining the criteria for selecting a proton pump 62(suppl 2):24-30.
References inhibitor. Am J Med. 2004;117(5A):14S-22S. 9. Keating GM, Figgitt DP. Intravenous esomepra-
1. Bardou M, Toubouti Y, Benhaberou-Brun D, et al. 5. Devlin JW, Welage LS, Olsen KM. Proton pump zole. Drugs. 2004;64:875-882.
Meta-analysis: proton-pump inhibition in high- inhibitor formulary considerations in the acutely 10. Julapalli VR, Graham DY. Appropriate use of
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Aliment Pharmacol Ther. 2005;21:677-686. and available formulations. Ann Pharmacother. agement of bleeding peptic ulcer. Dig Dis Sci.
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Main Points
• Intravenous (IV) formulations of proton pump inhibitors (PPIs) improve the systemic bioavailability of PPI because the acidity of
the stomach and the upper duodenum and drug lability in this environment are avoided; thus, more drug is delivered to the site
of action during the first few days of therapy.
• The US Food and Drug Administration–approved indications are different for the IV PPIs; however, they all are probably effective
in the treatment of these medical conditions.
• Use of any of the injectable PPIs is contraindicated in patients with known hypersensitivity to the drug and any of the formula-
tion ingredients.
• Treatment with the IV formulations of esomeprazole, lansoprazole, and pantoprazole should be discontinued as soon as the patient
is able to resume treatment with an oral PPI; symptomatic response to therapy with any PPI does not preclude the presence of
gastric malignancy; the safety and effectiveness of any of these PPIs has not been established in pediatric patients.
• All 3 of these PPIs are well tolerated: common adverse events included headache, flatulence, nausea, dyspepsia, and abdominal
pain; reactions specific to the IV route have included mild itching at the injection site and mild focal erythema at the IV inser-
tion site.
• Changes in pH might influence the absorption of some drugs from the stomach; PPIs might decrease the absorption of keto-
conazole, ampicillin esters, and iron salts and increase the absorption of benzyl penicillin by raising the pH of the stomach.

VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS 33

Intravenous PPIs continued

12. Wyeth Laboratories. Package Literature for intravenous (IV) lansoprazole are therapeutically travenous dosage forms of pantoprazole are
Protonix Delayed-Release Tablets. Madison, NJ: equivalent in suppressing gastric acid secretion equivalent in their ability to suppress gastric acid
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34 VOL. 6 NO. 1 2006 REVIEWS IN GASTROENTEROLOGICAL DISORDERS