(omeprazole)
Delayed-Release Capsules
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNING
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
The active ingredient in PRILOSEC* (omeprazole) Delayed-Release Capsules is a substituted
benzimidazole, 5-methoxy-2[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl] 1H–
benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a moleculear weight of 345.42. The structural formula is:
Omeprazole is a white to off-white crystalline powder which melts with decomposition at about
155oC. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone
and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of
pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.
PRILOSEC is supplied as delayed-release capsules for oral administration. Each delayed-release capsule contains either 10 mg or 20 mg of omeprazole in the form of enteric-coated
granules with the following inactive ingredients: cellulose, disodium hydrogen phosphate,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, mannitol, sodium lauryl sulfate
and other ingredients. The capsule shells have the following inactive ingredients: gelatin-NF,
FD&C; Blue #1, FD&C; Red #40, D&C; Red #28, titanium dioxide, synthetic black iron oxide,
isopropanol, butyl alcohol, FD&C; Blue #2, D&C; Red #7 Calcium Lake, and, in addition, the 10 mg
capsule shell also contains D&C; Yellow #10.
Pharmacokinetics and Metabolism: Omeprazole
PRILOSEC Delayed-Release Capsules contain an enteric-coated granule formulation of
omeprazole (because omeprazole is acid labile), so that absorption of omeprazole begins only
after the granules leave the stomach. Absorption is rapid with peak plasma levels 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 to 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. Protein
binding is approximately 95%.
The bioavailability of omeprazole increases slightly upon repeated administration of PRILOSEC
Delayed-Release Capsules.
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.
In patients with chronic hepatic disease, the bioavailability increased to approximately 100%
compared to an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the
drug increased to nearly 3 hours compared to the half life in normals of 0.5-1 hour. Plasma
clearance averaged 70 mL/min, compared to a value of 500-600 mL/min in normal subjects.
In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62
mL/min/1.73m2, 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.
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 volunteers.
In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of
approximately four-fold was noted in Asian subjects compared to Caucasians.
Dose adjustment, particularly where maintenance of healing of erosive esophagitis is indicated,
for the hepatically impaired and Asain subjects should be considered.
Pharmacokinetics: Combination Therapy
with Clarithromycin
Omprazole 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 T1/2 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 co-administered with
clarithromycin.
The plasma levels of clarithromycin and 14-hydroxyclarithromycin 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-hydroxyclarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57%
greater, and the mean AUC0-8 was 45 % greater. Clairitromycin concentrations in the gastric
tissue and mucus were also increased by concomitant administration of omeprazole.
Clarithromycin Tissue Concentrations
2 hour after dose1
Clarithromycin +
Tissue Clarithromycin Omeprazole
Antrum 10.48 +\- 2.01 (n=5) 19.96 +\- 4.71 (n=5)
Fundus 20.81 +\- 7.64 (n=5) 24.25 +\- 6.37 (n=5)
Mucus 4.15 +\- 7.74 (n=4) 39.29 +\- 32.79 (n=4)
1Mean +\- SD (ug/g)
For information on clarithromycin pharmacokinetics and microbiology, consult the clarithromycin
package insert, CLINICAL PHARMACOLOGY section.
Pharmacodynamics
Mechanism of Action
Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles,
that do not exhibit anticholinergic or H2 histamine antagonistic 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 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-related and
leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found
within the gastric mucosa for a day or more.
Antisecretory Activity
After oral administration, the onset of the antisecretory affect of omeprazole occurs within one
hour, with the maximum effect occuring within two hours. Inhibition of secretion is about 50% of
maximum at 24 hours and the duration of inhibitation lasts up to 72 hours. The antisecretory
effect thus lasts far longer than would be expected from the very short (less than one hour)
plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When
the drug is discontinued, secretary activity returns gradually, over 3 to 5 days. The inhibitory
effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a
plateau after 4 days.
Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg
of omeprazole in normal volunteers and patients are shown below. The “max” value represents
determinations at a time of maximum effect (2-6 hours after dosing), while “min” values are those
24 hours after the last dose of omeprazole.
Range of Mean Values from Multiple Studies
of the Mean Antisecretory Effects of Omeprazole
After Multiple Daily Dosing
Omeprazole Omeprazole
Parameter 20 mg 40 mg
% Decrease in Max Min Max Min
Basal Acid Output 78* 58-80 94* 80-93
% Decrease in
Peak Acid Output 79* 50-59 88* 62-68
% Decrease in
24-hour Intragastric 80-97 92-94
Acidity
*Single Studies
Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced
100% inhibition of 24-hour intragastric acidity in some patients.
Enterochromaffin-like (ECL) Cell Effects
In 24 month carcinogenicity studies in rats, a dose related significant increase in gastric carcinoid
tumors and ECL cell hyperplasia was observed in both male and female animals (see
PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility). Hypergastrinemia
secondary to prolonged and sustained hypochlorhydria has been postulted to be the mechanisms
by which ECL cell hyperplasia and gastric carcinoid tumors develop. Omeprazole may also
affect other cells in the gastrointestinal tract (e.g., G cells) either directly or by inducing sustained
hypochlorhydria, but this possibility has not been extensively studied.
Human gastric biopsy specimens from about 200 patients treated continuously with omeprazole
for an average of over 12 months have not detected ECL cell effects of omeprazole similar to
those seen in rats. Longer term data are needed to rule out the possibility of an increased risk
for the development of gastric tumors in patients receiving long-term therapy with omeprazole.
Serum Gastrin Effects
In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2
weeks of once daily administration of therapeutic doses of omeprazole in parallel with inhibition of
acid secretion. No further increase in serum gastrin occurred with continued treatment. In
comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg
doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values
returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.
Other Effects
Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not
been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no
effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone,
cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretion.
No effect on gastric emptying of the solid and liquid components of a test meal was
demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single IV dose of
omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose
dependent effect has been observed on basal or stimulated pepsin output in humans.
However,
when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin
activity is decreased.
As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy
subjects produced a significant increase in the intragastric concentrations of viable bacteria. The
pattern of the bacterial species was unchanged from that commonly found in saliva. All changes
resolved within three days of stopping treatment.
Clinical Studies
Duodenal Ulcer Disease
Active Duodenal Ulcer: in a multicenter, double-blind, placebo-controlled study of 147 patients
with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol)
at 2 to 4 weeks was significantly higher with PRILOSEC 20 mg once a day than with placebo (p < or = 0.01).
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC Placebo
20 mg a.m. a.m.
(n=99) (n=48)
Week 2 *41 13
Week 4 *75 27
*(p < or = 0.01)
Complete daytime and nighttime pain relief occurred significantly faster (P < or =0.01) in patients treated
with PRILOSEC 20 mg than in patients treated with placebo. At the end of the study,
significantly more patients who had received PRILOSEC had complete relief of daytime pain
(p < or = 0.05) and nighttime pain (p < or =0.01).
In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal
ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with
PRILOSEC 20 mg once a day than with ranitidine 150 mg b.i.d.(p<101)
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC Ranitidine
20 mg a.m. 150 mg b.i.d
(n=145) (n=148)
Week 2 42 34
Week 4 *82 63
*(p<0.01)
Healing occurred significantly faster in patients treated with PRILOSEC than in those treated with
ranitidine 150 mg b.i.d (p<0.01).
in a foreign multinational randomized, double-blind study of 105 patients with endoscopically
documented duodenal ulcer, 20 mg and 40 mg of PRILOSEC were compared to 150 mg b.i.d.
of ranitidine at 2,4, and 8 weeks. At 2 and 4 weeks both doses of PRILOSEC were statistically
superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of PRILOSEC and at 8
weeks there was no significant difference between any of the active drugs.
Treatment of Active Duodenal Ulcer
% of Patients Healed
PRILOSEC Ranitidine
20 mg 40 mg 150 mg b.i.d.
(n=34) (n=36) (n=35)
Week 2 *83 *83 53
Week 4 *97 *100 82
Week 8 100 100 94
*(p < or = 0.01)
Duodenal Ulcer Recurrence
Four randomized double blind clinical studies in patients with H. pylori infection and active
duodenal ulcer disease compared omeprazole plus clarithromycin to omeprazole. Two of these
studies, one in the U.S, the other in the U.S and Canada, included a clarithromycin alone arm.
The dose regimen in the two multicenter U.S studies (n=498) was PRILOSEEC 40 mg q.d. plus
clarithromyci 500 mg t.i.d. for 14 days followed by PRILOSEC 20 mg q.d. for 14 days; PRILOSEC 40 mg q.d. for 14 days followed by
PRILOSEC 20 mg q.d. for 14 days; clarithromycin 500 mg t.i.d. for 14 days. Two foreign studies
(n=369) compared PRILOSEC and clarithromycin to PRILOSEC, and did not include a
clarithromycin alone arm. The dose regimen was the same as that used in the U.S studies
except for one study (M92-812b) where PRILOSEC 40 mg q.d. was used throughout the 28 day
treatment period. Endpoints studied were: eradication of H. pylori, duodenal ulcer healing and
recurrence. H. pylori status was determined by histology and another bacteriological test. For a
given patient, H. pylori was considered eradicated if at least one of these tests was negative,
and none was positive.
The combination of omeprazole and clarithromycin was effective in eradicating H. pylori.
H. pylori Eradication Rates
% of Patients Curedt [95% Confidence Interval]
PRILOSEC +
Clarithromycin PRILOSEC Clarithromycin
U.S Studies
Study M93-067 *74 [61,85] 0 [0,6] 34 [20,50]
(n=58) (n=55) (n=44)
Study M93-100 *64 [51,76] 0 [0,6] 38 [24,53]
(n=64) (n=62) (n=48)
Non U.S Studies
Study M92-81b *83 [72,91] 1 [0,7] N/A
(n=69) (n=75)
Study M93-058 *74 [64,83] 4 [1,10] N/A
(n=93) (n=96)
t Evaluable patients with confirmed duodenal
ulcer and H. Pylori infection at baseline who are
healed at week 4 and for whom results were available for
the 4-6 week post-treatment visit are
included in this analysis.
* (p < or = 0.01)
Ulcer healing was not significantly different when clarithromycin was added to omeprazole
therapy compared to omeprazole therapy alone.
The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and
reduced duodenal ulcer recurrence.
Duodenal Ulcer Recurrence Rates by
H. pylori Eradication Status
% of Patients with Ulcer Recurrence
H. pylori H. pylori not
eradicated # eradicated #
U.S Studies t
6 months post-treatment
Study M93-067 *35 60
(n=49) (n=88)
Study M93-100 *8 60
(n=53) (n=106)
Non U.S. Studies tt
6 months post treatment
Study M92-81b *5 46
(n=43) (n=78)
Study M93-058 *6 43
(n=53) (n=107)
12 months post-treatment
Study M92-812b *5 68
(n=39) (n=71)
# H. pylori eradication status assessed at
same timepoint as ulcer recurrence.
t Combined results for PRILOSEC + clarithromycin,
PRILOSEC, and clarithromycin treatment arms
tt (p 0.01) versus proportion with duodenal ulcer
recurrence who were not H. Pylori eradicated
* (p < or = 0.01) versus proportion with
duodenal ulcer recurrence who were not H. pylori eradicated
Gastric Ulcer
In a U.S multicenter, double-blind, study of omeprazole 40 mg once a day, 20 mg once a day,
and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results
were obtained.
Treatment of gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC PRILOSEC
20 mg q.d. 40 mg q.d. Placebo
(n=202) (n=214) (n=104)
Week 4 47.5** 55.6** 30.8
Week 8 74.8** 82.7**,+ 48.1
** (p<0.01) PRILOSEC mg versus rantidine
+ (p<0.05) PRILOSEC 40 mg versus 20 mg
For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effe
ctive than 20 mg at 8 weeks.
In a foreign, multinational, double-blind study of 602 patints with endoscopically diagnosed gastric ulcer, omeprazole 40 mg once a day, 20 mg once a day, and ranitidine 150 mg twice a day were evaluated.
Treatment of Gastric Ulcer
% of Patients Healed
(All Patients Treated)
PRILOSEC PRILOSEC Ranitidine
20 mg q.d. 40 mg q.d. 150 mg b.i.d.
(n=200) (n=187) (n=199)
Week 4 63.5 78.1**,++ 56.3
Week 8 81.5 91.4**,++ 78.4
** (p<0.01) PRILOSEC 40 mg versus ranitidine
++ (p<0.01) PRILOSEC 40 mg versus 20 mg
Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
A placebo controlled study was conducted in Scandinavia to comapre the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis. Results are shown bel
ow.
% Successful Symptomatic Outcomea
PRILOSEC PRILOSEC Placebo
20 mg a.m. 10 mg a.m. a.m.
All patients 46*,t 31t 13
(n=205) (n=199) (n=105)
Patients with 56*,t 36t 14
Confirmed (n=115) (n=109) (n=59)
GERD
a Defined as complete resolution of heartburn
* (p < 0.005) versus 10 mg
t (p < 0.005) versus placebo
Erosive Esophagitis
In a U.S multicenter double-blind placebo controlled study of 20 mg or 40 mg of PRILOSEC
Delayed-Release Capsules in patients with symptoms of GERD and endoscopically
diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol)
were as follows:
20mg 40mg
PRILOSEC PRILOSEC Placebo
Week (n=83) (n=87) (N=43)
4 39** 45** 7
8 74** 75** 14
**(p<0.01)PRILOSEC versus placebo.
In this study, the 40 mg dose was not superior to the 20 mg dose of PRILOSEC in the
percentage healing rate. Other controlled clinical trials have also shown that PRILOSEC is
effective in severe GERD. In comparisons with histamine grade 2 or above, PRILOSEC in a
dose of 20 mg was significantly more effective than theactive controls. Complete daytime and
nighttime heartburn relief occurred significantly faster (0.01) in patients treated with PRILOSEC
than in those taking placebo or histamine H2-receptor antagonists.
In this and five other GERD controlled studies, significantly more patients taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms then patients receiving placebo.
Long Term Maintenance Treatment of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of
PRILOSEC were studied in patients with endoscopically confirmed healed esophagitis. Results
to determine maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis PRILOSEC PRILOSEC 20 mg 3 days 20 mg q.d. per week Placebo (n=138) (n=137) (N=131)
Percent in endoscopic remission at 6 months *70 34 11 *(p < 0.01) PRILOSEC 20 mg q.d. versus PRILOSEC 20 mg 3 consecutive days per week or placebo.
In an international multicenter double-blind study, PRILOSEC 20 mg daily and 10 mg daily were
compared to ranitidine 150 mg twice daily in patients with endoscopically confirmed healed
esophagitis. The table below provides the results of this study for maintenance of healing
of erosive esophagitis.
Life Table Analysis PRILOSEC PRILOSEC Ranitidine 20 mg q.d. per week Placebo (n=131) (n=133) (N=128)
Percent in endoscopic remission at 12 months 77* 58++ 46 *(p=0.01) PRILOSEC 20 mg q.d. versus PRILOSEC 10 mg or Ranitidine.
++(p=0.03) PRILOSEC 10 mg q.d. versus Ranitidine.
In patients who initially had grades 3 or 4 erosive esophagitis, for maintenace after healing 20
mg daily of PRILOSEC was effective, while 10 mg did not demonstrate effectiveness.
Pathological Hypersecretory Conditions
In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-
Ellison (ZE) syndrome with or without multiple endocrine adenomas, PRILOSEC Delayed-
Release Capsules significantly inhibited gastric acid secretion and controlled associated
symptoms of diarrhea, anorexia and pain. Doses ranging from 20 mg every other day to 360 mg
per day maintained basal acid secretion below 10 mEQ/hr in patients without prior gastric
surgery, and below 5 mEq/hr in patients with prior gastric surgery.
Initial doses were titrated to the individual patient need, and adjustments were necessary with
time in some patients (see DOSAGE AND ADMINISTRATION). PRILOSEC was well tolerated at
these high dose levels for prolonged periods (>5 years in some patients). In most ZE patients,
serum gastrin levels were not modified by PRILOSEC. However, in some patients serum gastrin
increased to levels greater than those present prior to initiation of omeprazole therapy. At least
11 patients with ZE syndrome on long-term treatment with PRILOSEC developed gastric
carcinoids. These findings are believed to be a manifestation of the underlying condition, which
is known to be associated with such tumors, rather than the result of the administation of
PRILOSEC. (see ADVERSE REACTIONS.)
Duodenal Ulcer
PRILOSEC Delayed-Release Capsules are indicated for short-term treatment of active duodenal
ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks
of therapy.
PRILOSEC Delayed-Release Capsules in combination with clarithromycin are also indicated for
treatment of patietns with H. Pylori infection and active duodenal ulcer to eradicate H. Pylori.
Eradication of H. Pylori has been shown to reduce the risk of duodenal ulcer recurrence (see
CLINICAL PHARMACOLOGY, Clinical Studies and DOSAGE AND ADMINISTRATION).
In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin
is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should
be instituted. (see the clarithromycin package insert, MICROBIOLOGY section.)
Gasric Ulcer
PRILOSEC Delayed-Release Capsules are indicated for short-term treatment (4-8 weeks) of
active benign gastric ulcer. (see CLINICAL PHARMACOLOGY, Clinical Studies, Gastric Ulcer.)
Treatment of Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
PRILOSEC Delayed-Release Capsules are indicated for the treatment of heartburn and other symptoms associated with GERD.
Erosive Esophagitis
PRILOSEC Delayed Release Capsules are indicated for the short term treatment (4 to 8 weeks)
of erosive esophagitis which has been diagnosed by endoscopy (see CLINICAL
PHARMACOLOGY, Clinical Studies).
The efficacy of PRILOSEC used for longer than 8 weeks in these patients has not been
established. In the rare instances of a patient not responding to 8 weeks of treatment, it may be
helpful to give up to an additional 4 weeks of treatment. If there is recurrence of erosive
esophagitis or GERD symptoms (e.g. heartburn) , additional
4-8 week courses of omeprazole may be considered.
Maintenance of Healing of Erosive Esophagitis
PRILOSEC Delayed-Release Capsules are indicated to maintain healing of erosive esophagitis.
Controlled studies do not extend beyond 12 months.
Pathological Hypersecretory Conditions
PRILOSEC Delayed-Release Capsules are indicated for the long-term treatment of pathological
hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and
systemic mastocytosis.)
Omeprazole
PRILOSEC Delayed-Release Capsules are contraindicated in patients with known hypersensitivity
to any component of the formulation.
Clarithromycin
Clarithromycin is contraindicated in patients with a known hypersensitivity to any macrolide
antibiotic.
Concomitant administration of clarithromycin with cisapride, pimozide, or terfenadine is contraindicated. There have been post-marketing reports of drug interaction when clarithromycin and/or erythromycin are co-administered with cisapride, pimozide, or
terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of hepatic metabolism of these drugs by erythromycin and clarithromycin. Fatalities h
ave been reported. (Please refer to full prescribing information for clarithromycin before prescribing.
Clarithromycin
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF
PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE
APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. (See WARNINGS in prescribing
information for clarithromycin.)
General
Symptomatic response to therapy with omeprazole does not preclude the presence of gastric
malignancy.
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated
long-term with omeprazole.
Information for Patients
PRILOSEC Delayed-Release Capsules should be taken before eating. Patients should be
cautioned that the PRILOSEC Delayed-Release Capsule should not be opened, chewed or
crushed, and should be swallowed whole.
Drug Interactions
Other
Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are
metabolized by oxidation in the liver. Although in normal subjects no interaction with
theophylline or propranolol was found, there have been clinical reports of interaction with other
drugs metabolized via the cytochrome P-450 system (e.g., clyclosporin, disulfiram,
benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the
dosage of these drugs when taken concomitantly with PRILOSEC.
Because of its profound and long-lasting inhibitation of gastric acid secretion, it is theoretically
possible that omeprazole may interfere with absorption of drugs where gastric pH is an important
determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, and iron salts). In the
clinical trials, antacids were used concomitantly with the administration of PRILOSEC.
Combination Therapy with Clarithromycin
Co-administration of omeprazole and clarithromycin may result in increases in plasma levels of
omeprazole, clarithromycin, and 14-hydroxy-clarithromycin. (See also CLINICAL
PHARMACOLOGY, Pharmacokinetics: Combination Therapy with Clarithromycin.)
Concomitant administration of clarithromycin with cisapride, pimozide, or terfenadine is contraindicated.
There have been reports of an interaction between erythromycin and astemizole resulting in QT prolongation and torsades de pointes. Concomitant administration of erythromycin and astemizole is contraindicated. Because clarithromycin is also metabolized
by cytochrome P450, concomitant administration of clarithromycin with astemizole is not recommended. (See also CONTRAINDICATIONS, Clarithromycin, above. Please refer to full prescribing information for clarithromycin before prescribing.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
In two, 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0
and 140.8 mg/kg/day (approximately 4 to 352 times the human dose, based on a patient weight
of 50 kg and human dose of 20 mg) produced gastric ECL cell carcinoids in a dose-related
manner in both male and female rats; the incidence of this effect was markedly higher in female
rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the
untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes.
In one of these studies, female rats were treated with 13.8 mg omeprazole kg/day
(approximately 35 times the human dose) for one year, then followed for an additional year
without the drug. No carcinoids were seen in these rats. An increaed incidence of treatment
related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls).
By the second year the difference between treated and control rats was much smaller (46% vs
26%) but still showed more hyperplasia in the treated group. An unusual primary malignant
tumor in the stomach was seen in one rat (2%). No similar tumor was seen in male or female
rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a
finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study
of omeprazole did not show increased tumor occurrence, but the study was not conclusive.
Omeprazole was not mutagenic in an in vitro Ames Salmonella typhimurium assay, an in vitro
mouse lymphoma cell assay and an in vivo rat liver DNA damage assay. A mouse
micronucleus test at 625 and 6250 times the human dose gave a borderline result, as did an in
vivo bone marrow chromosome aberration test. A second mouse micronucleus study at 2000
times the human dose, but with different (suboptimal) sampling times, was negative.
In a rat fertility and general reproductive performance test, omepazole in a dose range of 13.8 to
138.0 mg/kg/day (approximately 35 to 345 times the human dose) was not toxic or deleterious to
the reporductive performance of parental animals.
Pregnancy
Omeprazole
Pregnancy Category C
Teratology studies conducted in pregnant rats at doses up to 138 mg/kg/day (approximately 172
times the human dose) did not disclose any evidence for a teratogenic potential of omeprazole.
In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (approximately 17 to 172 times
the human dose) produced dose-related increases in embryo-lethality, fetal resorptions and
pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental
toxicity were observed in offspring resulting from parents treated with omeprazole 13.8 to 138.0
mg/kg/day (approximately 35 to 345 times the human dose). There are no adequate or well-
controlled studies in pregnant women. Sporadic reports have been received of congenital
abnormalities occuring in infants born to women who have received omeprazole during
pregnancy. Omeprazole should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Clarithromycin
Pregnancy Category C. See WARNINGS (above) and full prescribing information for
clarithromycin before using in pregnant women.
Nursing Mothers
It is not known whether omeprazole is excreted in human milk. In rats, omeprazole
administration during late gestation and lactation at doses of 13.8 to 138 mg/kg/day (35 to 345
times the human dose) resulted in decreased weight gain in pups. Because many drugs are
excreted in human milk, because of the potential for serious adverse reaction in nursing infants
from omeprazole, and because of the potential for tumorigenicity shown for omeprazole in rat
carcinogenicity studies, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children have not been established.
PRILOSEC Delayed-Release Capsules were generally well-tolerated during domestic and
international clinical trials in 3096 patients.
In the U.S. clinical trial population of 465 patients (including duodenal ulcer, Zollinger-Ellison
syndrome and resistant ulcer patients), the following adverse experiences were reported to occur
in 1% or more of patients on therapy with PRILOSEC. Numbers in parentheses indicate
percentages of the adverse experiences considered by investigators as possibly, probably or
definitely related to the drug:
Omeprazole placebo Ranitidine
(n=465) (n=64) (n=195)
Headache 6.9 (2.4) 6.3 7.7 (2.6)
Diarrhea 3.0 (1.9) 3.1 (1.6) 2.1 (0.5)
Abdominal Pain 2.4 (0.4) 3.1 2.1
Nausea 2.2 (0.9) 3.1 4.1 (0.5)
URI 1.9 1.6 2.6
Dizziness 1.5 (0.6) 0.0 2.6 (1.0)
Vomiting 1.5 (0.4) 4.7 1.5 (0.5)
Rash 1.5 (1.1) 0.0 0.0
Constipation 1.1 (0.9) 0.0 0.0
Cough 1.1 0.0 1.5
Asthenia 1.1 (0.2) 1.6 (1.6) 1.5 (1.0)
Back Pain 1.1 0.0 0.5
The following adverse reactions which occurred in 1% or more of omeprazole-treated patients have been reported in
international double-blind, and open-label, clinical trials in which 2,631 patients and subjects
received omeprazole.
Experience >/=1%
Casual Relationship not Assessed
Omeprazole Placebo
(n=2631) (n=20)
Body as a Whole, site
unspecified
Abdominal pain 5.2 3.3
Asthenia 1.3 0.8
Digestive System
Constipation 1.5 0.8
Diarrhea 3.7 2.5
Flatulence 2.7 5.8
Nausea 4.0 6.7
Vomiting 3.2 10.0
Acid regurgitation 1.9 3.3
Nervous System/Psychiatric
Headache 2.9 2.5
Additional adverse experiences occurring in 1% of patients or subjects in domestic and or
international trials, or occurring since the drug was marketed, are shown below within each body
system. In many instances, the relationship to PRILOSEC was unclear.
pressure, peripheral edema
esophageal candidiasis, mucosal atrophy of the tongue, dry mouth. During treatment with
omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and
appear to be reversible when treatment is discontinued.
Gastro-duodenal carcinoids have been reported in patients with ZE syndrome on long-term
treatment with PRILOSEC. This finding is believed to be a manifestation of the underlying
condition, which is known to be associated with such tumors.
marked elevations of liver function tests [ALT (SGPT), AST (SGOT), glutamyl transpeptidase
alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred,
including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic
failure (some fatal), and hepatic encephalopathy.
hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream
abnormalities, vertigo; paresthesia; hemifacial dysesthesia
necrolysis (TEN; some fatal), Stevens-Johnson syndrome, and erythema multiforme (some
severe); skin inflammation, urticaria, angioedema, pruritus, alopecia, dry skin, hyperhidrosis
microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria,
glycosuria, testicular pain, gynecomastia
neutropenia, anemia, leucocytosis, and hemolytic anemia have been reported.
The incidence of clinical adverse experiences in patients greater than 65 years of age was
similar to that in patients 65 years of age or less.
Combination Therapy with Clarithromycin
In clinical trials using combination therapy with PRILOSEC and clarithromycin, no adverse
experiences peculiar to this drug combination have been observed. Adverse experiences that
have occurred have been limited to those that have been previously reported with omeprazole or
clarithromycin.
Adverse experiences observed in controlled clinical trials using combination therapy with
PRILOSEC and clarithromycin (n=346) which differed from those previously described for
omeprazole alone were: Taste perversion (15%) tongue discoloration (2%), rhinitis (2%),
pharyngitis (1%) and flu syndrome (1%).
For more information on clarithromycin, refer to the
clarithromlycin package insert, ADVERSE RETIONS section.
Rare reports have been received of overdosage with omeprazole. Doses ranged from 320mg to
900 mg (16-45 times the usual recommended clinical dose.) Manifestations were variable, but
included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing,
headache, and dry mouth. Symptoms were transient and no serious clinical outcome has been
reported. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively
protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment
should be symptomatic and supportive.
Lethal doses of omeprazole after single oral administration are about 1500 mg/kg in mice and
greater than 40 mg/kg in rats given single intravenous infections. Animals given these doses
showed sedation, ptosis, convulsions, and decreased activity, body temperature and respiratory
rate and increased depth of respiration.
Duodenal Ulcer
Short-Term Treatment of Active Duodenal Ulcer: The recommended adult oral dose of PRILOSEC
is 20 mg once daily. Most patients heal within four weeks. Some patients may require an
additional four weeks of therapy. (See INDICATIONS AND USAGE.)
Reduction of the Risk of Duodenal Ulcer Recurrence: Combination Therapy with Clarithromlycin
Days 1-14: Days 15-28:
PRILOSEC 40 mg q.d. (in the PRILOSEC 20 mg q.d. morning) plus clarithromycin 500 mg t.i.d.
Please refer to clarithromycin full prescribing information for CONTRAINDICATIONS and
WARNING, and for information regarding dosing in elderly and renally impaired patients
(PRECAUTIONS: General, PRECAUTIONS: Geriatric Use and PRECAUTIONS: Drug
Interactions).
Gastric Ulcer
The recommended adult oral dose is 40 mg once a day for 4-8 weeks. (See CLINICAL
PHARMACOLOGY, Clinical Studies, Gastric Ulcer, and INDICATIONS AND USAGE, Gastric
Ulcer.)
Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal legions is 20 mg daily for up to 4 weeks. the recommended adult oral dose for the treatment of patients with erosive esophagitis and accompanying symptom
s due to GERD is 20 mg daily for 4 to 8 weeks. (See INDICATIONS AND USAGE.)
Maintenance of Healing of Erosive Esophagitis
The recommended adult oral dose is 20 mg daily. (See CLINICAL PHARMACOLOGY, Clinical
Studies.)
Pathological Hypersecretory Conditions
The dosage of PRILOSEC in patients with pathological hypersecretory conditions varies with the
individual patient. The recommended adult oral starting dose is 60 mg once a day. Doses
should be adjusted to individual patient needs and should continue for as long as clinically
indicated. Doses up to 120 mg t.i.d. have been administered. Daily dosages of greater than 80
mg should be administered in divided doses. Some patients with Zolinger-Ellison syndrome have
been treated continuously with PRILOSEC for more than 5 years. No dosage adjustment is
necessary for patients with renal impairment, hepatic dysfunction or for the eldely.
PRILOSEC Delayed-Release Capsules should be taken before eating. In the clinical trials,
antacids were used concomitantly with PRILOSEC.
Patients should be cautioned that the PRILOSEC Delayed-Release Capsule should not be
opened, chewed or crushed, and should be swallowed whole.
No.3426 — PRILOSEC Delayed-Release Capsules, 10 mg, are opaque, hard gelatin, apricot and
amethyst colored capsules, coded 606 on cap and PRILOSEC 10 on the body. They are
supplied as follows:
NDC 61113-606-31 unit of use bottles of 30
NDC 61113-606-68 bottles of 100
NDC 61113-606-28 unit dose packages of 100.
No.3440 — PRILOSEC Delayed-Release Capsules, 20 mg, are opaque hard gelatin, amethyst
colored capsules, coded 742 on cap and PRILOSEC 20 on body. They are supplied as follows:
NDC 61113-742-31 unit of use bottles of 30
(6505-01-314-2716, 20 mg 30’s)
NDC 61113-742-28 unit dose package of 100
(6505-01-314-2717, 20 mg individually sealed 100’s)
NDC 61113-742-82 bottles of 1000.
Storage
Store PRILOSEC Delayed-Release Capsules in a tight container protected from light and
moisture. Store between 15oC and 30oC (59oF and 86oF).
Dist. By:
Astra Merck
Wayne, PA 19087, USA
Manufactured by: Merck & CO., Inc., West Point, PA 19486, USA
Issued February 1997
Printed in USA