A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Prevacid Pharmacology, Pharmacokinetics, Studies, Metabolism - Lansoprazole
Prevacid Pharmacology, Pharmacokinetics, Studies, Metabolism - Lansoprazole
CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
Lansoprazole delayed-release capsules contain an enteric-coated
granule formulation of lansoprazole. Absorption of lansoprazole
begins only after the granules leave the stomach. Absorption is
rapid, with mean peak plasma
levels of lansoprazole
occurring after approximately 1.7 hours. Peak plasma concentrations
of lansoprazole
(Cmax) and the area
under plasma concentration curve
(AUC) of lansoprazole
are approximately proportional in doses from 15 mg
to 60 mg after single-oral
administration. Lansoprazole does not accumulate and its pharmacokinetics
are unaltered by multiple dosing.
Absorption: The absorption
of lansoprazole
is rapid, with mean Cmax occurring approximately 1.7
hours after oral dosing,
and relatively complete with absolute
bioavailability over 80%. In
healthy subjects, the mean
(± SD) plasma
half-life was 1.5 (± 1.0) hours.
Both Cmax and AUC
are diminished by about 50% if the drug
is given 30 minutes after food as opposed to the fasting
condition. There is no significant
food effect if the drug
is given before meals.
Distribution: Lansoprazole is 97% bound
plasma proteins. Plasma
protein binding is constant
over the concentration
range of 0.05 to 5.0 mcg/ml.
Metabolism: Lansoprazole is extensively metabolized
in the liver. Two metabolites have been identified in measurable
quantities in plasma
(the hydroxylated sulfinyl and sulfone
derivatives of lansoprazole). These metabolites have very little
or no antisecretory activity. Lansoprazole is thought to be transformed
into two active species
which inhibit acid secretion by (H+,K+)-ATPase
within the parietal
cell canaliculus, but are not present
in the systemic circulation.
The plasma elimination half-life
of lansoprazole
does not reflect its duration
of suppression of gastric
acid secretion. Thus, the
plasma elimination
half-life is less than two hours, while the acid
inhibitory effect lasts
more than 24 hours.
Elimination: Following single-dose oral
administration of lansoprazole, virtually no unchanged lansoprazole
was excreted in the urine. In
one study, after a single oral
dose of 14C-lansoprazole,
approximately one-third of the administered radiation
was excreted in the urine and two-thirds was recovered in the feces.
This implies a significant biliary excretion
of the metabolites of lansoprazole.
Special Populations
Geriatric: The clearance
of lansoprazole
is decreased in the elderly, with elimination
half-life increased
approximately 50% to 100%. Because the mean
half-life in the elderly
remains between 1.9 to 2.9 hours, repeated once daily dosing does
not result in accumulation of lansoprazole. Peak plasma
levels were not increased in the elderly.
Pediatric: The pharmacokinetics
of lansoprazole
has not been investigated in patients <18 years of age.
Gender: In
a study comparing 12 male
and six female human
subjects, no gender differences
were found in pharmacokinetics
and intragastric pH results (also see PRECAUTIONS,
Use in Women).
Renal Insufficiency: In
patients with severe renal
insufficiency, plasma protein
binding decreased by 1.0%-1.5% after administration
of 60 mg of lansoprazole. Patients with renal
insufficiency had a shortened elimination half-life and decreased
total AUC (free and bound).
AUC for free lansoprazole
in plasma, however, was not related to the degree
of renal impairment, and
Cmax and Tmax were not different from subjects
with healthy kidneys.
Hepatic Insufficiency: In
patients with various degrees of chronic
hepatic disease, the
mean plasma
half-life of the drug
was prolonged from 1.5 hours to 3.2-7.2 hours. An
increase in mean AUC
of up to 500% was observed at steady state
in hepatically-impaired patients compared to healthy subjects. Dose
reduction in patients
with severe hepatic
disease should be considered.
Race: The pooled mean
pharmacokinetic parameters of lansoprazole from twelve U.S. Phase
1 studies (N=513) were compared to the mean
pharmacokinetic parameters from two Asian studies (N=20). The mean
AUCs of lansoprazole in Asian subjects were approximately twice
those seen in pooled U.S. data; however, the inter-individual variability
was high. The Cmax values were comparable.
Pharmacodynamics
Mechanism of Action
Lansoprazole belongs to a class
of antisecretory compounds, the substituted benzimidazoles, that
do not exhibit anticholinergic
or histamine H2-receptor
antagonist properties, but that suppress gastric
acid secretion
by specific inhibition of the (H+,K+)-ATPase
enzyme system
at the secretory surface
of the gastric parietal
cell. Because this enzyme system is regarded as the acid
(proton) pump within the
parietal cell, lansoprazole
has been characterized as a gastric
acid-pump inhibitor, in that it blocks the final step
of acid production. This
effect is dose-related
and leads to inhibition
of both basal and stimulated
gastric acid
secretion irrespective of the stimulus.
Antisecretory Activity
After oral administration,
lansoprazole was
shown to significantly decrease the basal
acid output
and significantly increase the mean
gastric pH
and percent of time the
gastric pH
was >3 and >4. Lansoprazole also significantly reduced meal-stimulated
gastric acid
output and secretion
volume, as well as pentagastrin-stimulated acid
output. In patients with
hypersecretion of acid, lansoprazole
significantly reduced basal
and pentagastrin-stimulated gastric acid
secretion. Lansoprazole inhibited the normal
increases in secretion volume, acidity and acid
output induced
by insulin.
In a crossover study
comparing lansoprazole
15 and 30 mg with omeprazole
20 mg for five days, the
effects on intragastric
pH are shown inTABLE 1.
| TABLE 1 Mean Antisecretory Effects
after Single and Multiple Daily Dosing |
| |
|
Lansoprazole |
Omeprazole |
| |
Baseline |
15 mg |
30 mg |
20 mg |
| Parameter |
Value |
Day 1 |
Day 5 |
Day 1 |
Day 5 |
Day 1 |
Day 5 |
| Mean 24-hr pH |
2.1 |
2.7† |
4.0† |
3.6* |
4.9* |
2.5 |
4.2† |
| Mean Nighttime pH |
1.9 |
2.4 |
3.0† |
2.6 |
3.8* |
2.2 |
3.0† |
| % Time Gastric pH>3 |
18 |
33† |
59† |
51* |
72* |
30† |
61† |
| % Time Gastric pH>4 |
12 |
22† |
49† |
41* |
66* |
19 |
51† |
| * (p<0.05) versus baseline,
lansoprazole 15 mg
and omeprazole
20 mg. |
| † (p<005) versus baseline
only. |
| NOTE: An
intragastric
pH of >4 reflects
a reduction
in gastric acid
by 99%. |
After the initial dose
in this study, increased gastric
pH was seen within 1-2 hours
with lansoprazole
30 mg, 2-3 hours with lansoprazole
15 mg, and 3-4 hours with omeprazole
20 mg. After multiple
daily dosing, increased gastric pH
was seen within the first hour postdosing with lansoprazole 30 mg
and within 1-2 hours postdosing with lansoprazole
15 mg and omeprazole 20 mg.
Acid suppression
may enhance the effect
of antimicrobials in eradicating Helicobacter pylori (H. pylori).
The percentage of time
gastric pH
was elevated above 5 and 6 was evaluated in a crossover
study of lansoprazole given qd, bid and tid.
| TABLE 2 Mean Antisecretory Effects
After 5 Days of Bid and Tid Dosing |
| |
Lansoprazole |
| Parameter |
30 mg
qd |
15 mg
bid |
30 mg
bid |
30 mg
tid |
| % Time Gastric pH>5 |
43 |
47 |
59* |
77† |
| % Time Gastric pH>6 |
20 |
23 |
28 |
45† |
| * (p<0.05) versus lansoprazole
30 mg qd. |
| † (p<0.05) versus lansoprazole
30 mg qd, 15 mg bid
and 30 mg bid. |
The inhibition of
gastric acid
secretion as measured
by intragastric pH returns gradually to normal
over two to four days after multiple
doses. There is no indication
of rebound gastric
acidity.
Enterochromaffin-Like (ECL) Cell Effects
During lifetime exposure
of rats with up to 150 mg/kg/day of lansoprazole dosed seven days
per week, marked hypergastrinemia
was observed followed by ECL cell
proliferation
and formation of carcinoid
tumors, especially in female
rats (see PRECAUTIONS, Carcinogenesis,
Mutagenesis, and Impairment of Fertility) .
Gastric biopsy specimens from the body of the stomach
from approximately 150 patients treated continuously with lansoprazole
for at least one year have not shown evidence
of ECL cell effects similar
to those seen in rat studies. Longer term
data are needed to rule
out the possibility of an increased risk
of the development
of gastric tumors in
patients receiving long-term therapy with lansoprazole.
Other Gastric Effects in Humans
Lansoprazole did not significantly affect
mucosal blood wflow
in the fundus of the stomach. Due to the normal, physiologic effect
caused by the inhibition
of gastric acid
secretion, a decrease of about 17% in blood flow in the antrum,
pylorus, and duodenal
bulb was seen. Lansoprazole
significantly slowed the gastric
emptying of digestible
solids. Lansoprazole increased serum pepsinogen
levels and decreased pepsin
activity under basal conditions
and in response to
meal stimulation
or insulin injection.
As with other agents that
elevate intragastric
pH, increases in gastric
pH were associated with increases
in nitrate-reducing bacteria
and elevation of nitrate
concentration in gastric
juice in patients with
gastric ulcer. No significant
increase in nitrosamine concentrations was observed.
Serum Gastrin Effects
In over 2100 patients, median
fasting serum
gastrin levels increased
50% to 100% from baseline, but remained within normal
range after treatment
with lansoprazole
given orally in doses of 15 mg
to 60 mg. These elevations reached a plateau
within two months of therapy and returned to pretreatment levels
within four weeks after discontinuation of therapy.
Endocrine Effects
Human studies for up to one year have not detected any clinically
significant effects in the endocrine
system. Hormones studied include testosterone, luteinizing hormone
(LH), follicle stimulating
hormone (FSH), sex
hormone binding globulin
(SHBG), dehydroepiandrosterone
sulfate (DHEA-S), prolactin,
cortisol, estradiol, insulin, aldosterone, parathormone, glucagon,
thyroid stimulating hormone
(TSH), triiodothyronine
(T3), thyroxine (T4), and somatotropic
hormone (STH). Lansoprazole
in oral doses of 15 to
60 mg for up to one year
had no clinically significant
effect on sexual function.
In addition, lansoprazole
in oral doses of 15 to
60 mg for two to eight weeks had no clinically significant
effect on thyroid function.
In 24-month carcinogenicity studies on Sprague-Dawley rats with
daily dosages up to 150 mg/kg, proliferative changes in the Leydig
cells of the testes, including benign
neoplasm, were increased compared to control
rates.
Other Effects
No systemic effects
of lansoprazole
on the central nervous
system, lymphoid, hematopoietic, renal, hepatic, cardiovascular
or respiratory systems have been found in humans. No visual
toxicity was observed among 56 patients who had extensive baseline
eye evaluations, were treated
with up to 180 mg/day of lansoprazole
and were observed for up to 58 months. Other rat-specific findings
after lifetime exposure
included focal pancreatic
atrophy, diffuse lymphoid hyperplasia
in the thymus, and spontaneous
retinal atrophy.
Microbiology
Lansoprazole, clarithromycin and/or amoxicillin
have been shown to be active against most strains of Helicobacter
pylori in vitro and in clinical
infections as described in INDICATIONS
AND USAGE.
Helicobacter pylori
Pretreatment Resistance: Clarithromycin pretreatment
resistance (³ 2.0 mcg/ml)
was 9.5% (91/960) by E-test and 11.3% (12/106) by agar
dilution in the dual
and triple therapy clinical
trials (M93-125, M93-130, M93-131, M95-392, and M95-399).
Amoxicillin pretreatment
susceptible isolates
(£ 0.25 mcg/ml)
occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in
the dual and triple therapy
clinical trials by E-test and agar
dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test
and 2 of 100 patients (2.0%) by agar
dilution had amoxicillin
pretreatment MICs of > 0.25 mcg/ml.
One patient on the 14 day triple
therapy regimen had
an unconfirmed pretreatment
amoxicillin minimum inhibitory concentration
(MIC) of > 256 mcg/ml by E-test and
the patient was eradicated
of H. pylori.. See TABLE 3
| TABLE 3 Clarithromycin Susceptibility
Test Results and Clinical/Bacteriological Outcomes* |
| Clarithromycin Pretreatment Results |
Clarithromycin Post-treatment Results |
| |
|
H. pylori negative-eradicated |
H. pylori positive-not eradicated |
| |
|
|
Post-treatment susceptibility results |
| |
|
|
S† |
I† |
R† |
No MIC |
| Triple Therapy 14-Day‡ |
|
|
112 |
105 |
|
|
|
7 |
|
|
3 |
3 |
|
|
|
|
|
|
17 |
6 |
|
|
7 |
4 |
| Triple Therapy 10-Day§ |
|
|
42 |
40 |
1 |
|
1 |
|
|
|
|
|
|
|
|
|
|
|
4 |
1 |
|
|
3 |
|
| * Includes only patients with
pretreatment clarithromycin susceptibility test
results. |
| † Susceptible (S) MIC
£ 0.25 mcg/ml, Intermediate
(I) MIC 0.5 - 1.0
mcg/ml, Resistant (R) MIC
³ 2 mcg/ml. |
| ‡ Lansoprazole 30 mg
bid/amoxicillin 1 gm bid/clarithromycin 500 mg
bid (M95-399, M93-131, M95-392). |
| § Lansoprazole 30 mg
bid/amoxicillin 1 gm bid/clarithromycin 500 mg
bid (M95-399). |
Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin
triple therapy will likely
have clarithromycin resistant H. pylori. Therefore, for those patients
who fail therapy, clarithromycin susceptibility testing should be
done when possible. Patients with clarithromycin resistant H. pylori
should not be treated with lansoprazole/amoxicillin/clarithromycin
triple therapy or with regimens which include clarithromycin as
the sole antimicrobial agent.
Amoxicillin Susceptibility Test Results and Clinical/Bacteriological
Outcomes
In the dual and triple
therapy clinical trials,
82.6% (195/236) of the patients that had pretreatment
amoxicillin susceptible
MICs (£ 0.25 mcg/ml) were eradicated
of H. pylori. Of those with pretreatment
amoxicillin MICs of > 0.25 mcg/ml, three of six had the H. pylori
eradicated. A total of 30% (21/70) of the patients failed lansoprazole
30 mg tid/amoxicillin 1 gm
tid dual therapy and a total of 12.8% (22/172) of the patients failed
the 10-and-14 day triple
therapy regimens. Post-treatment susceptibility results were not
obtained on 11 of the patients who failed therapy. Nine of the 11
patients with amoxicillin
post-treatment MICs that failed the triple therapy regimen
also had clarithromycin resistant H. pylori isolates.
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H. pylori
is agar dilution MICs.1
One to three microliters of an inoculum equivalent to a No. 2 McFarland
standard (1 ´
107 - 1 ´
108 CFU/ml for H. pylori) are inoculated directly onto
freshly prepared antimicrobial
containing Mueller-Hinton agar
plates with 5% aged defibrinated sheep blood
(³2 weeks old). The agar
dilution plates are
incubated at 35°C in a microaerobic environment produced by
a gas generating system
suitable for campylobacters. After 3 days of incubation, the MICs
are recorded as the lowest concentration of antimicrobial
agent required to inhibit
growth of the organism.
The clarithromycin and amoxicillin
MIC values should be interpreted
according to the criteria shown in TABLE 4.
| TABLE 4 |
| Clarithromycin MIC
(mcg/ml)* |
Interpretation |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| * These are tentative
breakpoints for the agar dilution
methodology and they should not be used to interpret results
obtained using alternative methods. |
| † There were not enough organisms
with MICs >0.25 mcg/ml to determine a resistance
breakpoint. |
Standardized susceptibility test
procedures require the use of laboratory control microorganisms
to control the technical
aspects of the laboratory procedures. Standard clarithromycin and
amoxicillin powders
should provide the MIC values
shown in TABLE 5.
| TABLE 5 |
| Microorganism |
Antimicrobial Agent |
MIC (mcg/ml)* |
|
|
|
0.015-0.12 mcg/ml |
|
|
|
0.015-0.12 mcg/ml |
| * These are quality control
ranges for the agar
dilution methodology
and they should not be used to control
test results obtained using alternative methods. |
CLINICAL STUDIES
Duodenal Ulcer
In a U.S. multicenter, double-blind, placebo-controlled, dose-response
(15, 30, and 60 mg of lansoprazole
once daily) study of 284 patients with endoscopically documented
duodenal ulcer, the
percentage of patients healed after two and four weeks was significantly
higher with all doses of lansoprazole than with placebo. There was
no evidence of a greater
or earlier response with the two higher doses compared with lansoprazole
15 mg. Based on this study and the second study described below,
the recommended dose of
lansoprazole in duodenal
ulcer is 15 mg
per day. (See TABLE 6)
| TABLE 6 Duodenal Ulcer Healing
Rates |
| |
Lansoprazole |
Placebo |
| |
15 mg
qd |
30 mg
qd |
60 mg
qd |
|
| Week |
(N=68) |
(N=74) |
(N=70) |
(N=72) |
| 2 |
42.4%* |
35.6%* |
39.1%* |
11.3% |
| 4 |
89.4%* |
91.7%* |
89.9%* |
46.1% |
| * (p£0.001)
versus placebo. |
Lansoprazole 15 mg was significantly
more effective than placebo
in relieving day and nighttime abdominal
pain and in decreasing
the amount of antacid
taken per day.
In a second U.S. multicenter study, also double-blind, placebo-controlled,
dose-comparison (15 and 30 mg
of lansoprazole
once daily), and including a comparison with ranitidine, in 280
patients with endoscopically documented duodenal ulcer, the percentage
of patients healed after four weeks was significantly higher with
both doses of lansoprazole
than with placebo. There was no evidence
of a greater or earlier response
with the higher dose of lansoprazole. Although the 15 mg
dose of lansoprazole
was superior to ranitidine at 4 weeks, the lack of significant
difference at 2 weeks and the absence
of a difference between 30 mg
of lansoprazole
and ranitidine leaves the comparative effectiveness
of the two agents undetermined. (See TABLE 7)
| TABLE 7 Duodenal Ulcer Healing
Rates |
| |
Lansoprazole |
Ranitidine |
Placebo |
| |
15 mg
qd |
30 mg
qd |
300 mg
h.s. |
|
| Week |
(N=80) |
(N=77) |
(N=82) |
(N=41) |
| 2 |
35.0% |
44.2% |
30.5%* |
34.2% |
| 4 |
92.3%† |
80.3%* |
70.5%* |
47.5% |
| * (p£0.001)
versus placebo. |
| † (p£0.05)
versus placebo
and ranitidine. |
H. Pylori Eradication to Reduce the Risk of Duodenal Ulcer
Recurrence
Randomized, double-blind clinical
studies performed in the U.S. in patients with H. pylori and duodenal
ulcer disease
(defined as an active ulcer
or history of an ulcer
within one year) evaluated the efficacy of lansoprazole in combination
with amoxicillin
capsules and clarithromycin tablets as triple 14-day therapy or
in combination with amoxicillin
capsules as dual 14-day therapy for the eradication
of H. pylori. Based on the results of these studies, the safety
and efficacy of two different eradication
regimens were established:
Triple Therapy: Lansoprazole 30 mg
bid/amoxicillin 1 gm bid/clarithromycin 500 mg
bid.
Dual Therapy: Lansoprazole 30 mg
tid/amoxicillin 1 gm tid.
All treatments were for 14 days. H. pylori eradication
was defined as two negative
tests (culture and histology) at 4-6 weeks following the end of
treatment.
Triple therapy was shown to be more effective than all possible
dual therapy combinations (see TABLE 8). Dual therapy was shown
to be more effective than both monotherapies (see TABLE 9) . Eradication
of H. pylori has been shown to reduce
the risk of duodenal
ulcer recurrence.
| TABLE 8 H. pylori Eradication
Rates¾Triple Therapy (lomeprazole/amoxicillin/clarithromycin)
Percent of Patients Cured [95% Confidence Interval] (Number
of patients) |
| Study |
Duration |
Triple Therapy Evaluable Analysis* |
Triple Therapy Intent-to-Treat Analysis† |
| M93-131 |
14 days |
92‡ |
86‡ |
| |
|
[80.0-97.7] |
[73.3-93.5] |
| |
|
(N=48) |
(N=55) |
| M95-392 |
14 days |
86§ |
83§ |
| |
|
[75.7-93.6] |
[72.0-90.8] |
| |
|
(N=66) |
(N=70) |
| M95-399|| |
14 days |
85 |
82 |
| |
|
[77.0-91.0] |
[73.9-88.1] |
| |
|
(N=113) |
(N=126 |
| |
10 days |
84 |
81 |
| |
|
[76.0-89.8] |
[73.9-87.6] |
| |
|
(N=123) |
(N=135) |
| * Based on evaluable patients
with confirmed duodenal ulcer
(active or within one year) and H. pylori infection
at baseline defined as at least two of three positive
endoscopic tests from CLOtest (Delta West Ltd., Bentley, Australia),
histology and/or culture. Patients were included in the analysis
if they completed the study. Additionally, if patients dropped
out of the study due to an adverse event related to the study
drug, they were included in the analysis
as failures of therapy. |
| † Patients were included in
the analysis if they had documented H. pylori infection
at baseline as
defined above and had a confirmed duodenal
ulcer (active or
within one year). All dropouts were included as failures of
therapy. |
| ‡ (p<0.05) versus lansoprazole/amoxicillin
and lansoprazole/clarithromycin dual therapy. |
| § (p<0.05) versus clarithromycin/amoxicillin
dual therapy. |
| || The 95% confidence interval
for the difference in eradication
rates, 10-day minus 14-day is (-10.5, 8.1) in the evaluable
analysis and
(-9.7, 9.1) in the intent-to-treat analysis. |
| TABLE 9 H. pylori Eradication
Rates¾14-Day Dual Therapy
(lansoprazole/amoxicillin) Percent of Patients Cured [95%
Confidence Interval] (Number of patients) |
| Study |
Dual Therapy Evaluable Analysis* |
Dual Therapy Intent-to-Treat Analysis† |
| M93-131 |
77‡ |
70‡ |
| |
[62.5-87.2] |
[56.8-81.2] |
| |
(N=51) |
(N=60) |
| M95-125 |
66§ |
61§ |
| |
[51.9-77.5] |
[48.5-72.9] |
| |
(N=58) |
(N=67) |
| * Based on evaluable patients
with confirmed duodenal ulcer
(active or within one year) and H. pylori infection
at baseline defined as at least two of three positive
endoscopic tests from CLOtest, histology and/or culture. Patients
were included in the analysis
if they completed the study. Additionally, if patients dropped
out of the study due to an adverse event related to the study
drug, they were included in the analysis
as failures of therapy. |
| † Patients were included in
the analysis if they had documented H. pylori infection
at baseline as
defined above and had a confirmed duodenal
ulcer (active or
within one year). All dropouts were included as failures of
therapy. |
| ‡ (p<0.05) versus lansoprazole
alone. |
| § (p<0.05) versus lansoprazole
alone or amoxicillin
alone. |
A randomized, double-blind clinical
study performed in the U.S. in patients with H. pylori and duodenal
ulcer disease
(defined as an active ulcer
or history of an ulcer
within one year) compared the efficacy of lansoprazole triple therapy
for 10 and 14 days. This study established that the 10-day triple
therapy was equivalent
to the 14-day triple
therapy in eradicating H. pylori.
Long-Term Maintenance Treatment of Duodenal Ulcers
Lansoprazole has been shown to prevent the recurrence
of duodenal ulcers.
Two independent, double-blind, multicenter, controlled trials were
conducted in patients with endoscopically confirmed healed duodenal
ulcers. Patients remained healed significantly longer and the number
of recurrences of duodenal ulcers was significantly less in patients
treated with lansoprazole
than in patients treated with placebo
over a 12-month period. See TABLE 10.
| TABLE 10 Endoscopic Remission
Rates |
| |
|
|
Percent in Endoscopic Remission |
| Trial |
Drug |
No. of Pts. |
0-3 mo. |
0-6 mo. |
0-12 mo. |
| #1 |
Lansoprazole 15 mg
qd |
86 |
90%* |
87%* |
84%* |
| |
Placebo |
83 |
49% |
41% |
39% |
| #2 |
Lansoprazole 30 mg
qd |
18 |
94%* |
94%* |
85%* |
| |
Lansoprazole 15 mg
qd |
15 |
87%* |
79%* |
70%* |
| |
Placebo |
15 |
33% |
0% |
0% |
| % Life Table Estimate |
| * (p£0.001)
versus placebo. |
In trial #2, no significant
difference was noted between lansoprazole 15 mg
and 30 mg in maintaining
remission.
Gastric Ulcer
In a U.S. multicenter, double-blind, placebo-controlled study of
253 patients with endoscopically documented gastric
ulcer, the percentage of patients healed at four and eight weeks
was significantly higher with lansoprazole 15 mg
and 30 mg once a day than
with placebo. See TABLE 11.
| TABLE 11 Gastric Ulcer Healing
Rates |
| |
Lansoprazole |
Placebo |
| Week |
15 mg
qd |
30 mg
qd |
60 mg
qd |
|
| |
(N=65) |
(N=63) |
(N=61) |
(N=64) |
| 4 |
64.6%* |
58.1%* |
53.3%* |
37.5% |
| 8 |
92.2%* |
96.8%* |
93.2%* |
76.7% |
| * (p£0.05)
versus placebo. |
Patients treated with any lansoprazole
dose reported significantly
less day and night abdominal
pain along with fewer days
of antacid use and fewer
antacid tablets used per
day than the placebo
group.
Independent substantiation of the effectiveness
of lansoprazole
30 mg was provided by a meta-analysis
of published and unpublished data.
Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD: In
a U.S. multicenter, double-blind, placebo-controlled study of 214
patients with frequent GERD
symptoms, but no esophageal
erosions by endoscopy, significantly greater relief
of heartburn associated with GERD
was observed with the administration
of lansoprazole 15 mg once
daily up to 8 weeks than with placebo. No significant
additional benefit from lansoprazole
30 mg once daily was observed.
The intent-to-treat analyses demonstrated significant
reduction in frequency
and severity of day and night heartburn. Data for frequency and
severity for the 8-week treatment
period are found in TABLE
12.
| TABLE 12 Frequency of Heartburn |
| Variable |
Placebo (n=43) |
Lansoprazole 15 mg
(n=80) |
Lansoprazole 30 mg
(n=86) |
| % of Days Without Heartburn |
|
|
0% |
71%* |
46%* |
|
|
11% |
81%* |
76%* |
|
|
13% |
84%* |
82%* |
| % of Nights Without Heartburn |
|
|
17% |
86%* |
57%* |
|
|
25% |
89%* |
73%* |
|
|
36% |
92%* |
80%* |
| * (p < 0.01) versus placebo. |
Erosive Esophagitis
In a U.S. multicenter, double-blind, placebo-controlled study of
269 patients entering with an endoscopic diagnosis
of esophagitis with
mucosal grading of 2 or more and grades 3 and 4 signifying erosive
disease, the percentages of patients with healing
are in TABLE 13.
| TABLE 13 Erosive Esophagitis Healing
Rates |
| |
Lansoprazole |
Placebo |
| |
15 mg
qd |
30 mg
qd |
60 mg
qd |
|
| Week |
(N=69) |
(N=65) |
(N=72) |
(N=63) |
| 4 |
67.6%* |
81.3%† |
80.6%† |
32.8% |
| 6 |
87.7%* |
95.4%* |
94.3%* |
52.5% |
| 8 |
90.9%* |
95.4%* |
94.4%* |
52.5% |
| * (p£0.001)
versus placebo. |
| † (p£0.05)
versus lansoprazole
15 mg and placebo. |
In this study, all lansoprazole
groups reported significantly greater relief of heartburn
and less day and night abdominal
pain along with fewer days
of antacid use and fewer
antacid tablets taken
per day than the placebo
group.
Although all doses were effective, the earlier healing
in the higher two doses suggest 30 mg
qd as the recommended dose.
Lansoprazole was also compared in a U.S. multicenter, double-blind
study to a low dose of
ranitidine in 242 patients with erosive
reflux esophagitis. Lansoprazole
at a dose of 30 mg
was significantly more effective than ranitidine 150 mg
b.i.d. as shown in TABLE 14.
| TABLE 14 Erosive Esophagitis Healing
Rates |
| |
Lansoprazole 30 mg
qd (N=115) |
Ranitidine 150 mg
bid (N=127) |
| Week |
|
|
| 2 |
66.7%* |
38.7% |
| 4 |
82.5%* |
52.0% |
| 6 |
93.0%* |
67.8% |
| 8 |
92.1%* |
69.9% |
| * (p£0.001)
versus ranitidine. |
In addition, patients treated with lansoprazole
reported less day and nighttime heartburn
and took less antacid
tablets for fewer days than patients taking ranitidine 150 mg
bid.
Although this study demonstrates effectiveness
of lansoprazole
in healing erosive esophagitis, it does not represent an adequate
comparison with ranitidine because the recommended ranitidine dose
for esophagitis
is 150 mg q.i.d., twice the dose
used in this study.
In the two trials described and in several smaller studies involving
patients with moderate to severe erosive
esophagitis, lansoprazole
produced healing rates similar to those shown above.
In a U.S. multicenter, double-blind, active-controlled study, 30
mg of lansoprazole
was compared with ranitidine 150 mg
bid in 151 patients with erosive
reflux esophagitis
that was poorly responsive to a minimum of 12 weeks of treatment
with at least one H2-receptor antagonist given at the
dose indicated for symptom
relief or greater, namely
cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine
40 mg/day or nizatidine 300 mg/day. Lansoprazole 30 mg
was more effective than ranitidine 150 mg
bid in healing reflux
esophagitis and
the percentage of patients with healing were as follows. This study
does not constitute a comparison of the effectiveness of histamine
H2-receptor antagonists with lansoprazole, as all patients
had demonstrated unresponsiveness to the histamine
H2-receptor antagonist mode
of treatment. It does indicate, however, that lansoprazole may be
useful in patients failing on a histamine
H2-receptor antagonist (TABLE 15).
| TABLE 15 Reflux Esophagitis Healing
Rates in Patients Poorly Responsive to Histamine H2-Receptor
Antagonist Therapy |
| |
Lansoprazole |
Ranitidine |
| Week |
30 mg
qd (N=100) |
150 mg
bid (N=51) |
| 4 |
74.7%* |
42.6% |
| 8 |
83.7%* |
32.0% |
| * (p£0.001)
versus ranitidine. |
Long-Term Maintenance Treatment of Erosive Esophagitis
Two independent, double-blind, multicenter, controlled trials were
conducted in patients with endoscopically confirmed healed esophagitis.
Patients remained in remission
significantly longer and the number
of recurrences of erosive
esophagitis was
significantly less in patients treated with lansoprazole than in
patients treated with placebo
over a 12-month period. See TABLE 16.
| TABLE 16 Endoscopic Remission
Rates |
| |
|
|
Percent in Endoscopic Remission |
| Trial |
Drug |
No. of Pts. |
0-3 mo. |
0-6 mo. |
0-12 mo. |
| #1 |
Lansoprazole 15 mg
qd |
59 |
83%* |
81%* |
79%* |
| |
Lansoprazole 30 mg
qd |
56 |
93%* |
93%* |
90%* |
| |
Placebo |
55 |
31% |
27% |
24% |
| #2 |
Lansoprazole 15 mg
qd |
50 |
74%* |
72%* |
67%* |
| |
Lansoprazole 30 mg
qd |
49 |
75%* |
72%* |
55%* |
| |
Placebo |
47 |
16% |
13% |
13% |
| % Life Table Estimate. |
| * (p£0.001)
versus placebo. |
Regardless of initial
grade of erosive
esophagitis, lansoprazole
15 mg and 30 mg were similar
in maintaining remission.
Pathological Hypersecretory Conditions Including Zollinger-Ellison
Syndrome
In open studies of 57
patients with pathological hypersecretory conditions, such as Zollinger-Ellison
(ZE) syndrome with
or without multiple
endocrine adenomas, lansoprazole
significantly inhibited gastric
acid secretion
and controlled associated symptoms of diarrhea, anorexia
and pain. Doses ranging from 15 mg
every other day to 180 mg
per day maintained basal
acid secretion below 10
mEq/hr in patients without prior gastric
surgery, and below 5 m/Eq/hr in patients with prior gastric
surgery.
Initial dose were titrated
to the individual patient
need, and adjustments were necessary with time
in some patients (see DOSAGE AND ADMINISTRATION).
Lansoprazole was well tolerated at these high dose levels for prolonged
periods (greater than four years in some patients). In most ZE patients,
serum gastrin
levels were not modified by lansoprazole. However, in some patients
serum gastrin
increased to levels greater than those present
prior to initiation of lansoprazole
therapy.
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