Mechanism Of Action
Omeprazole is an antisecretory drug whereas
clarithromycin and amoxicillin are antibacterial drugs [See Microbiology].
Pharmacokinetics when all three of the Omeclamox®-Pak components
were coadministered has not been studied. Studies have shown the low risk of
clinically significant interactions of omeprazole and amoxicillin or omeprazole
and clarithromycin when administered together. There is no information about
the gastric mucosal concentrations of omeprazole, clarithromycin and
amoxicillin after administration of these drugs concomitantly. The systemic
pharmacokinetic information presented below is based on studies in which each
product was administered alone, or in combination of two components.
Omeprazole Delayed-Release Capsules, USP
Absorption And Distribution
Omeprazole delayed-release capsules contain an
enteric-coated granule formulation of omeprazole (because omeprazole is
acidlabile), so that absorption of omeprazole begins only after the granules
leave the stomach. Absorption is rapid, with peak plasma concentrations of
omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of
omeprazole and AUC are approximately proportional to doses up to 40 mg, but
because of a saturable first-pass effect, a greater than linear response in
peak plasma concentration and AUC occurs with doses greater than 40 mg.
Absolute bioavailability (compared with intravenous administration) is about
30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In
healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body
clearance is 500-600 mL/min.
The bioavailability of omeprazole increases slightly upon
repeated administration of omeprazole delayed-release capsules.
Omeprazole delayed-release capsules 40 mg was
bioequivalent when administered with and without applesauce. However, omeprazole
delayed-release capsules 20 mg was not bioequivalent when administered with and
without applesauce. When administered with applesauce, a mean 25% reduction in
Cmax was observed without a significant change in AUC for omeprazole delayed-release
capsules 20 mg. The clinical relevance of this finding is unknown. Protein
binding is approximately 95%.
Metabolism And Excretion
Omeprazole is extensively metabolized by the cytochrome
P450 (CYP) enzyme system. Following single dose oral administration of a buffered
solution of omeprazole, little if any unchanged drug was excreted in urine. The
majority of the dose (about 77%) was eliminated in urine as at least six
metabolites. Two were identified as hydroxyomeprazole and the corresponding
carboxylic acid. The remainder of the dose was recoverable in feces. This
implies a significant biliary excretion of the metabolites of omeprazole. Three
metabolites have been identified in plasma – the sulfide and sulfone
derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very
little or no antisecretory activity.
The elimination rate of omeprazole was somewhat decreased
in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable
when a single 40 mg oral dose of omeprazole (buffered solution) was
administered to healthy elderly volunteers, versus 58% in young volunteers
given the same dose. Nearly 70% of the dose was recovered in urine as
metabolites of omeprazole and no unchanged drug was detected. The plasma
clearance of omeprazole was 250 mL/min (about half that of young volunteers)
and its plasma half-life averaged one hour, about twice that of young healthy
In patients with chronic hepatic disease, the
bioavailability of omeprazole increased to approximately 100% compared with an
IV dose, reflecting decreased first-pass effect, and the plasma half-life of
the drug increased to nearly 3 hours compared with the half-life in normals of
0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a value of
500-600 mL/min in normal subjects. It is recommended to avoid the use of
Omeclamox®-Pak in patients with hepatic impairment.
In patients with chronic renal impairment, whose
creatinine clearance ranged between 10 and 62 mL/min/1.73m,2 the disposition of
omeprazole was very similar to that in healthy volunteers, although there was a
slight increase in bioavailability. Because urinary excretion is a primary
route of excretion of omeprazole metabolites, their elimination slowed in
proportion to the decreased creatinine clearance. No dose reduction is
necessary in patients with renal impairment.
In pharmacokinetic studies of single 20 mg omeprazole
doses, an increase in AUC of approximately four-fold was noted in Asian subjects
compared with Caucasians. It is recommended to avoid the use of Omeclamox®-Pak
in Asian patients unless it is deemed that the benefits outweigh the risks.
Clarithromycin Tablets, USP
Clarithromycin is rapidly absorbed from the
gastrointestinal tract after oral administration. The absolute bioavailability
of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg
dose of clarithromycin, food slightly delays the onset of clarithromycin
absorption, increasing the peak time from approximately 2 to 2.5 hours. Food
also increases the clarithromycin peak plasma concentration by about 24%, but
does not affect the extent of clarithromycin bioavailability. Food does not
affect the onset of formation of the antimicrobially active metabolite, 14-OH
clarithromycin or its peak plasma concentration but does slightly increase the
extent of metabolite formation, indicated by an 11% decrease in area under the
plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be
given without regard to food.
In nonfasting healthy human subjects (males and females),
peak plasma concentrations were attained within 2 to 3 hours after oral dosing.
Steady-state peak plasma clarithromycin concentrations were attained within 3
days and were approximately 3 to 4 μg/mL with a 500 mg dose administered
every 8 to 12 hours. The elimination half-life of clarithromycin was 5 to 7
hours with 500 mg administered every 8 to 12 hours. The nonlinearity of
clarithromycin pharmacokinetics is slight at the recommended dose of 500 mg administered
every 8 to 12 hours. With a 500 mg every 8 to 12 hours dosing, the peak
steady-state concentration of 14-OH clarithromycin is up to 1 μg/mL, and
its elimination half-life is about 7 to 9 hours. The steady-state concentration
of this metabolite is generally attained within 3 to 4 days.
After a 500 mg tablet every 12 hours, the urinary
excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin
approximates the normal glomerular filtration rate. The major metabolite found
in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15%
of the dose with a 500 mg tablet administered every 12 hours.
The steady-state concentrations of clarithromycin in
subjects with impaired hepatic function did not differ from those in normal subjects;
however, the 14-OH clarithromycin concentrations were lower in the hepatically
impaired subjects. The decreased formation of 14-OH clarithromycin was at least
partially offset by an increase in renal clearance of clarithromycin in the
subjects with impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was altered in
subjects with impaired renal function. In the presence of severe renal impairment
with or without coexisting hepatic impairment, prolonged dosing intervals for
clarithromycin may be appropriate.
Amoxicillin Capsules, USP
Amoxicillin is stable in the presence of gastric acid and
may be given without regard to meals. It is rapidly absorbed after oral administration.
It diffuses readily into most body tissues and fluids, with the exception of
brain and spinal fluid, except when meninges are inflamed. The half-life of
amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in
the urine; its excretion can be delayed by concurrent administration of
probenecid. In blood serum, amoxicillin is approximately 20% proteinbound.
Orally administered doses of 500 mg amoxicillin capsules
result in average peak blood concentrations 1 to 2 hours after administration in
the range of 5.5 μg /mL to 7.5 μg /mL. Detectable serum
concentrations are observed up to 8 hours after an orally administered dose of
amoxicillin. Approximately 60% of an orally administered dose of amoxicillin is
excreted in the urine within 6 to 8 hours.
Combination Therapy Of Omeprazole with Antimicrobials
Omeprazole 40 mg daily was given in combination with
clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady-state
plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and T½
increases of 30%, 89% and 34% respectively) by the concomitant administration
of clarithromycin. The observed increases in omeprazole plasma concentration
were associated with the following pharmacological effects. The mean 24-hour
gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when
coadministered with clarithromycin.
The plasma concentrations of clarithromycin and
14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole.
For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27%
greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered
with omeprazole than when clarithromycin was administered alone. Similar
results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater,
the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater.
Clarithromycin concentrations in the gastric tissue and mucus were also
increased by concomitant administration of omeprazole.
Table 1 : Mean ± SD Clarithromycin Tissue
Concentrations 2 hours after Dose
||Clarithromycin + Omeprazole (μg/g)
||10.48 ± 2.01 (n = 5)
||19.96 ± 4.71 (n=5)
||20.81 ± 7.64 (n = 5)
||24.25 ± 6.37 (n= 5)
||4.15 ± 7.74 (n = 4)
||39.29 ± 32.79 (n=4)
Antiretroviral Drugs and Omeprazole
The clinical importance and the mechanisms behind
interactions between omeprazole and antiretroviral drugs are not always known. Increased
gastric pH during omeprazole treatment may change the absorption of the
antiretroviral drug. Other possible interaction mechanisms are via inhibition
Following multiple doses of nelfinavir (1250 mg twice
daily) and omeprazole (40 mg once daily), AUC of nelfinavir and the M8 metabolite
was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%.
Following multiple doses of atazanavir (400 mg once
daily) and omeprazole (40 mg once daily 2 hours before atazanavir), AUC of atazanavir
was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration
with omeprazole and atazanavir is not recommended.
Saquinavir serum AUC, Cmax and Cmin increased by 82%, 75%
and 106%, respectively, following multiple dosing of saquinavir/ritonavir
(1000/100 mg) twice daily for 15 days with omeprazole 40 mg once daily
coadministered days 11 to 15 [See DRUG INTERACTIONS].
Cilostazol and Omeprazole
Omeprazole acts as an inhibitor of CYP2C19. Omeprazole,
given in doses of 40 mg daily for one week to 20 healthy subjects in crossover
study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax
and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7
times the activity of cilostazol, were increased by 29% and 69% respectively.
Co-administration of cilostazol with omeprazole is expected to increase
concentrations of cilostazol and its above mentioned active metabolite.
Therefore a dose reduction of cilostazol from 100 mg b.i.d. to 50 mg b.i.d.
should be considered [See DRUG INTERACTIONS].
Theophylline and Clarithromycin
Theophylline is metabolized by CYP1A2 and CYP3A4.
Clarithromycin will increase theophylline plasma concentrations when it is administered
concomitantly. In two studies in which theophylline was administered with
clarithromycin (theophylline sustainedrelease formulation dosed at either 6.5
mg/kg or 12 mg/kg together with 250 or 500 mg every 12 hours clarithromycin),
the steadystate Cmax, Cmin, and AUC of theophylline increased about 20%.
Monitoring of serum theophylline concentrations should be considered for
patients receiving high doses of theophylline or with baseline concentrations
in the upper therapeutic range [See DRUG INTERACTIONS].
Voriconazole And Omeprazole
Voriconazole is an inhibitor of CYP2C19, CYP2C9, and
CYP3A4. Coadministration of voriconazole and omeprazole will increase omeprazole
plasma exposure. When voriconazole (400 mg every 12 hours x 1 day, then 200 mg
x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy
subjects, it significantly increased the steady-state Cmax and AUC0-24 of
omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3,
4.4) respectively as compared to when omeprazole was given without voriconazole.
Dose adjustment of omeprazole is not normally required.
Administration of omeprazole 20 mg twice daily for 4 days
and a single 1000 mg dose of mycophenolate mofetil approximately one hour after
the last dose of omeprazole to 12 healthy subjects in a cross-over study
resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of
Mechanism Of Action
Omeprazole, an antisecretory drug with the substituted
benzimidazoles, suppresses 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 gastric mucosa, omeprazole has been characterized as a gastric acid-pump
inhibitor, in that it blocks the final step of acid production. This effect is
dose-dependent and leads to inhibition of both basal and stimulated acid
secretion irrespective of the stimulus. Omeprazole can also exhibit
anti-bacterial activity depending on the culture conditions. Animal studies
indicate that after rapid disappearance from plasma, omeprazole can be found
within the gastric mucosa for a day or more.
Clarithromycin exerts its antibacterial activity by
binding to the 50S ribosomal subunit of susceptible microorganisms resulting in
inhibition of protein synthesis.
Amoxicillin acts through the inhibition of biosynthesis
of cell wall mucopeptide.
Activity In Vitro And In Vivo
Triple therapy with omeprazole, clarithromycin and
amoxicillin has been shown to be active against most strains of Helicobacter pylori
in vitro and in clinical infections as indicated [See INDICATIONS AND USAGE].
In vitro studies show that chloramphenicol, macrolides,
sulfonamides, and tetracyclines may interfere with bactericidal effects of penicillin;
however, the clinical significance of this interaction is not well documented.
Helicobacter pylori Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 9.3%
(41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies [See
Amoxicillin pretreatment susceptible isolates ( ≤
0.25 μg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin
triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum
inhibitory concentrations (MICs) > 0.25 μg/mL occurred in 0.7% (3/439)
of the patients, all of whom were in the clarithromycin and amoxicillin study
arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory
concentration (MIC) of > 256 μg/mL by Etest.®
Table 2: Pre-treatment and post-treatment clarithromycin
susceptibility test results and clinical/bacteriological outcomes in patients treated
with triple therapy*
|Clarithromycin Pre-treatment Results
||H. pylori negative - eradicated
||Clarithromycin Post-treatment Results
|H. pylori positive - not eradicated Post-treatment susceptibility results
|aSusceptible (S) MIC ≤ 0.25 μg/mL,
Intermediate (I) MIC 0.5 μg/mL, Resistant (R) MIC ≥ 1 μg/mL.
*Treatment with omeprazole 20 mg twice daily/clarithromycin 500 mg twice
daily/amoxicillin 1 g twice daily for 10 days (Studies 1, 2 and 3) followed by
omeprazole 20 mg once daily for another 18 days (Studies 1 and 2).
Patients not eradicated of H. pylori following
omeprazole/clarithromycin/amoxicillin triple therapy will likely have
clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
susceptibility testing should be done, if possible. Patients with
clarithromycinresistant H. pylori should not be treated with any of the
following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/ amoxicillin
triple therapy, or other regimens which include clarithromycin as the sole
Amoxicillin Susceptibility Test Results And Clinical/Bacteriological
In the triple therapy clinical trials, 84.9% (157/185) of
the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had
pretreatment amoxicillin susceptible MICs ( ≤ 0.25 μg/mL) were
eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment susceptibility
test results and 17 had post-treatment H. pylori isolates with
amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy
also had post-treatment H. pylori isolates with clarithromycin resistant
Susceptibility Test For Helicobacter Pylori
The reference methodology for susceptibility testing of H.
pylori is agar dilution MICs [See REFERENCES]. One to three
microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 –
1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared
antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated
sheep blood ( ≥ 2 weeks old). The agar dilution plates are incubated at
35°C in a microaerobic environment produced by a gas generating system suitable
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 following criteria:
Table 3 : In vitro Susceptibility Interpretive
Criteria for Clarithromycin and Amoxicillin
|Clarithromvcin MIC (μg/mL)a
| ≤ 0.25
| ≥ 1.0
|Amoxicillin MIC (μg/mL)a,b
| ≤ 0.25
|aThese are breakpoints for the agar dilution
methodology and they should not be used to interpret results obtained using
bThere were not enough organisms with MICs > 0.25 μg/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 following MIC values:
Table 4 : Quality Control for Susceptibility Testing
|H. pylori ATCC 43504
|H. pylori ATCC 43504
|aThese are quality control ranges for the agar
dilution methodology and they should not be used to control test results obtained
using alternative methods.
Effects On Gastrointestinal Microbial Ecology
Decreased gastric acidity due to any means including
proton pump inhibitors, increases gastric counts of bacteria normally present
in the gastrointestinal tract. Treatment with proton pump inhibitors may lead
to slightly increased risk of gastrointestinal infections such as Salmonella
H. pylori Associated Duodenal Ulcer Disease
Three U.S., randomized, double-blind clinical studies in
patients with H. pylori infection and duodenal ulcer disease (n = 558) compared
omeprazole plus clarithromycin plus amoxicillin with clarithromycin plus
amoxicillin. Two studies (1 and 2) were conducted in patients with an active
duodenal ulcer, and the other study (3) was conducted in patients with a
history of a duodenal ulcer in the past 5 years but without an ulcer present at
the time of enrollment. The dose regimen in the studies was omeprazole 20 mg twice
daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily
for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice
daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen
also received an additional 18 days of omeprazole 20 mg once daily. Endpoints
studied were eradication of H. pylori and duodenal ulcer healing (studies
1 and 2 only). H. pylori status was determined by CLOtest,® histology
and culture in all three studies. For a given patient, H. pylori was considered
eradicated if at least two of these tests were negative and none was positive.
The combination of omeprazole plus clarithromycin plus
amoxicillin, was effective in eradicating H. pylori.
Table 5: Per-Protocol and Intent-to-Treat H.
pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
||omeprazole + clarithromycin + amozicillin
||carithromycin + amoxicillin
|Per - Protocol†
||Per - Protocol†
||Intent - to Treat‡
||*77 [64, 86]
||*69 [57, 79]
||43 [31, 56]
||37 [27, 48]
|(n = 64)
||(n = 80)
||(n = 67)
||(n = 84)
||*78 [67, 88]
||*73 [61, 82]
||41 [29, 54]
||36 [26, 47]
|(n = 65)
||(n = 77)
||(n = 68)
||(n = 83)
||*90 [80, 96]
||*83 [74, 91]
||33 [24, 44]
||32 [23, 42]
|(n = 69)
||(n = 84)
||(n = 93)
||(n = 99)
|†Patients were included in the analysis if they had confirmed
duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within
5 years, study 3) 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. The impact of eradication on ulcer recurrence has not been assessed in
patients with a past history of ulcer.
‡Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts
were included as failures of therapy.
*(p < 0.05) versus clarithromycin plus amoxicillin.
1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP.
The effects of penicillin and cephalosporin ingestions in children less than
six years of age. Vet Hum Toxicol. 1988;30:66-67.
2. Clinical Laboratory Standards Institute. Methods for
Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;
Approved Standard- Eighth Edition. CLSI document M07-A8. Wayne, PA: Clinical and
Laboratory Standards Institute; 2009.