HIGH
LIGHTS OF PRESCRIBING INFORMATION
These highlights
do
not include all the information needed to use
ZEGERID safely and effectively. See full prescribing information for
ZEGERID.
ZEGERID (omeprazole/sodium bicarbonate) powder for oral suspension ZEGERID (omeprazole/sodium bicarbonate) capsules
for oral use
Initial U.S. Approval: 2004
————–—————RECENT MAJOR
CHANGES————————–
Warnings and Precautions, Acute Interstitial Nephritis
(5.3) 12/2014 Warnings and Precautions, Cyanocobalamin
(Vitamin B-12) Deficiency (5.4) 12/2014
----------------------------INDICA
TIONS AND USAGE---------------------------
ZEGERID is a
proton pump inhibitor indicated for:
•
Short-term
treatment of
active duodenal ulcer
(1.1)
•
Short-term
treatment of
active benign gastric ulcer
(1.2)
•
Treatment of gastroesophageal reflux disease (GERD) (1.3)
• Maintenance of
healing of
erosive esophagitis
(1.4)
• Reduction of risk of upper GI bleeding in critically ill patients (1.5)
The safety and effectiveness of
ZEGERID in pediatric patients (<18 years of age) have not been established. (8.4)
----------------------DOSAG
E AND ADMINISTRATION-----------------------
•
Short-Term Treatment of Active Duodenal Ulcer: 20 mg once daily for 4 weeks (some patients may require an additional 4 weeks of therapy (14.1)) (2)
•
Gastric Ulcer: 40 mg once daily for 4-8 weeks
(2)
•
Gastroesophageal Reflux Disease (GERD) (2)
-
Symptomatic GERD (with no esophageal erosions): 20 mg once daily
for up to 4 weeks
- Erosive Esophagitis: 20 mg once daily for 4-8 weeks
• Maintenance of
Healing of
Erosive Esophagitis: 20 mg once daily*(2)
• Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill
Patients: (40mg oral suspension only) 40 mg initially followed by 40 mg
6-8 hours later and 40 mg daily thereafter
for
14
days (2)
*studied for 12 months
---------------------DOSAG
E FORMS
AND
STRENGTHS----------------------
•
ZEGERID is available as
a capsule and as a powder
for
oral suspension
in 20 mg and 40 mg strengths (3)
-------------------------------CON
TRAINDICATIONS-----------------------------
•
Known hypersensitivity to any components of
the formulation (4)
-----------------------WARNING
S AND PRECAUTIONS------------------------
• Concomitant Gastric Malignancy: Symptomatic response to therapy with ZEGERID does not preclude the presence of gastric malignancy
(5.1)
•
Atrophic Gastritis: Has been observed in gastric corpus biopsies from patients
treated long-term
with
omeprazole (5.2)
•
Acute interstitial nephritis has been observed in patients taking PPIs.
(5.3)
• Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g.,
longer than 3 years)
may
lead
to malabsorption or a deficiency of cyanocobalamin. (5.4)
• Buffer Content: contains
sodium bicarbonate (5.5)
•
PPI
therapy may be associated with increased risk ofClostridium difficileassociated diarrhea. (5.6)
•
Avoid concomitant use of
ZEGERID with clopidogrel (5.7)
• Bone Fracture: Long-term
and
multiple daily dose PPI therapy may be
associated with an increased risk for
osteoporosis-related fractures of
the hip, wrist, or spine. (5.8)
•
Hypomagnesemia has been reported rarely with prolonged treatment
with
PPIs (5.9)
•
Avoid concomitant use of
ZEGERID with St John’s
Wort or rifampin due to the potential reduction in omeprazole concentrations (5.10, 7.2)
•
Interactions with diagnostic investigations
for
Neuroendocrine Tumors:
Increases
in intragastric pH may result in hypergastrinemia and
enterochromaffin-like cell hyperplasia and increased Choromogranin A levels
which may interfere with diagnostic investigations
for
neuroendocrine tumors. (5.11, 12.2)
------------------------------ADV
ERSE REACTIONS-------------------------------
Most common adverse reactions (incidence ≥ 2%) are:
Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence (6)
To report SUSPECTED ADVERSE REACTIONS, contact Salix
Pharmaceuticals Inc. at 1-800-508-0024 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
------------------------------DRUG INTERACTIONS-------------------------------
• May interfere with drugs
for
which gastric pH can affect bioavailability
(e.g., ketoconazole, ampicillin esters, iron salts, erlotinib, digoxin, and
mycophenolate mofetil) (7.1)
•
Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): ZEGERID can
prolong their elimination. Monitor to determine the need for
possible
dose adjustments when taken with ZEGERID (7.2)
•
Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for
increases
in INR and prothrombin time (7.2)
•
Voriconazole: May increase plasma levels
of omeprazole (7.2)
•
Saquinavir: ZEGERID increases
plasma levels of
saquinavir (7.3)
•
ZEGERID may reduce plasma levels
of atazanavir and nelfinavir (7.3)
• Clopidogrel: Zegerid decreases exposure to the active metabolite of clopidogrel (7.5)
•
Tacrolimus: ZEGERID may increase serum levels
of tacrolimus
(7.6)
• Methotrexate: Zegerid may increase serum
level of methotrexate (7.8)
-----------------------US
E IN SPECIFIC POPULATIONS-----------------------
•
Pregnancy: Based upon animal data, may cause fetal harm (8.1)
•
The safety and effectiveness
of ZEGERID in pediatric patients
less
than
18 years of
age
have not been established. (8.4)
•
Hepatic Impairment: Consider
dose reduction, particularly for maintenance of
healing of
erosive esophagitis
(12.3)
S
ee 17 for PATIENT COUNSELING
INFORMATION and
Medication
Guide
Revised: 12/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Duodenal Ulcer
1.2 Gastric Ulcer
1.3 Treatment of
Gastroesophageal Reflux Disease (GERD)
1.4 Maintenance of
Healing of
Erosive Esophagitis
1.5 Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients (40mg suspension only)
2 DOSAGE AND
ADMINISTRATION
3 DOSAGE FORMS AND
STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Concomitant Gastric Malignancy
5.2 Atrophic Gastritis
5.3 Acute Interstitial Nephritis
5.4 Cyanocobalamin (vitamin B-12) Deficiency
5.5 Buffer Content
5.6 Clostridium DifficileAssociated Diarrhea
5.7 Interaction with Clopidogrel
5.8 Bone Fracture
5.9 Hypomagnesemia
5.10 Concomitant Use of
ZEGERID with St John’s
Wort or Rifampin
5.11 Interactions with Investigations for Neuroendocrine Tumors
5.12 Concomitant Use of ZEGERID with Methotrexate
6
ADVERSE REACTIONS
6.1 Clinical Trials
Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Drugs for Which Gastric pH Can Affect Bioavailability
7.2 Drugs Metabolized by Cytochrome P450 (CYP)
7.3 Antiretroviral Agents
7.4 Combination Therapy with Clarithromycin
7.5 Clopidogrel
7.6 Tacrolimus
7.7 Interactions With Investigations
of Neuroendocrine Tumors
7.8 Methotrexate
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
8.8 Asian Population
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism
of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
13.2 Animal Toxicology and/or
Pharmacology
14 CLINICAL STUDIES
14.1 Duodenal Ulcer
Disease
14.2 Gastric Ulcer
14.3 Gastroesophageal Reflux Disease GERD
14.4 Long Term
Maintenance Treatment of Erosive Esophagitis
14.5 Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
Sections
or subsections
omitted from
the
full prescribing information are
not listed.
FULL PRESCRIBING INFORMATION:
1 INDICATIONS AND USAGE
1.1 Duodenal Ulcer
ZEGERID (omeprazole/sodium bicarbonate)
is 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. [See Clinical
Studies (14.1)]
1.2 Gastr
ic Ulcer
ZEGERID is indicated for short-term
treatment (4-8 weeks)
of active benign gastric ulcer.[See Clinical Studies (14.2)]
1.3
Treatment
of Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
ZEGERID
is indicated for the treatment of heartburn and other
symptoms
associated with GERD for up to 4 weeks.[See Clinical Studies (14.3)]
Erosive Esophagitis
ZEGERID is indicated for
the short-term treatment (4-8 weeks) of
erosive esophagitis which has been diagnosed by endoscopy.
The efficacy of ZEGERID used for longer
than 8 weeks in these patients has not been established. If a patient does not respond 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 ZEGERID
may
be considered. [See Clinical
Studies (14.3)]
1.4 Ma
intenance of Healing of
Erosive Esophagitis
ZEGERID is indicated to maintain healing of
erosive esophagitis. Controlled studies do not extend beyond 12 months. [See Clinical Studies
(14.4)]
1.5 R
eduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients
(40mg oral suspension only)
ZEGERID Powder for Oral Suspension 40 mg/1680 mg is indicated for the reduction of
risk of
upper GI bleeding in critically ill patients.[See Clinical Studies, Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients (14.5)]
2
DOSAG
E AND ADMINISTRATION
ZEGERID (omeprazole/sodium bicarbonate)
is available as
a capsule and as
a powder for oral suspension in 20 mg and 40 mg strengths
of omeprazole for adult use. Directions for use for
each
indication are summarized in Table 1.
All recommended doses
throughout the labeling are based upon omeprazole.
Since both the 20 mg and 40 mg oral suspension packets contain the same amount of
sodium bicarbonate (1680 mg), two packets of
20
mg are not equivalent to one packet of
ZEGERID 40 mg; therefore, two 20 mg packets
of ZEGERID should not be substituted for one packet of
ZEGERID 40 mg.
Since both the 20 mg and 40 mg capsules contain the same amount of
sodium bicarbonate (1100 mg), two capsules
of 20 mg are not equivalent to one capsule of ZEGERID 40 mg; therefore, two 20 mg capsules
of ZEGERID should not be substituted for one capsule of ZEGERID 40 mg.
ZEGERID should be taken on an empty stomach at least one hour before a
meal.
For patients receiving continuous Nasogastric (NG)/ Orogastric (OG)
tube
feeding, enteral feeding should be suspended approximately 3 hours before
and
1 hour after
administration of
ZEGERID Powder for Oral Suspension.
Table 1: Recommended
Doses of ZEGERID by Indication for Adults 18 Years and
Older
|
Indication
|
Recommended Dose
|
Frequency
|
|
Short-Term
Treatment of Active Duodenal Ulcer
|
20 mg
|
Once daily for 4 weeks*,+
|
|
Benign Gastric Ulcer
|
40 mg
|
Once daily for 4-8 weeks **,+
|
|
Gastroesophageal Reflux Disease (GERD)
|
|
Symptomatic GERD (with no esophageal erosions)
Erosive Esophagitis
|
20 mg
20 mg
|
Once daily for up to 4 weeks+
Once daily for 4-8 weeks+
|
|
Maintenance of Healing of
Erosive Esophagitis
|
20 mg
|
Once daily**
|
|
Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients
(40 mg oral suspension only)
|
40 mg
|
40 mg initially followed by 40 mg 6-8 hours later and 40 mg daily thereafter for 14 days**
|
* Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of
therapy.[See Clinical Studies
(14.1)]
** Controlled studies do not extend beyond 12 months.[See Clinical Studies
(14)]
+ For additional information,[See Indications and Usage (1)]
SpecialPopulations
Hepatic Insufficiency
Consider dose reduction, particularly for
maintenance of healing of erosive
esophagitis.[See Clinical Pharmacology (12.3)]
Administration of
Capsules
ZEGERID Capsules should be swallowed intact with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.
Preparation and Administration of Suspension
Directions for use: Empty packet contents into a small cup containing 1-2 tablespoons
of water. DO NOT USE OTHER LIQUIDS
OR
FOODS. Stir well and drink immediately. Refill cup with water and drink.
If ZEGERID
is to be administered through a nasogastric (NG)
or orogastric (OG)
tube, the suspension should be constituted with approximately 20 mL of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and administer
immediately. An appropriately-sized syringe should be used to
instill the suspension in the tube. The suspension should be washed through
the
tube with 20 mL of water.
3
DOSAG
E FORMS AND STRENGTHS
ZEGERID 20-mg Capsules: Each opaque, hard gelatin, white capsule, imprinted with the Santarus logo and “20”, contains 20 mg omeprazole and 1100 mg sodium bicarbonate.
ZEGERID 40-mg Capsules: Each opaque, hard gelatin, colored dark blue
and
white capsule, imprinted with the Santarus logo and “40”, contains 40 mg
omeprazole and 1100 mg sodium bicarbonate.
ZEGERID Powder for Oral Suspension is a white, flavored powder
packaged in unit-dose packets. Each packet contains
either
20
mg or 40 mg omeprazole and 1680 mg sodium bicarbonate.
4
CON
TRAINDICATIONS
ZEGERID is contraindicated in patients
with
known hypersensitivity to any components of
the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria. [See Adverse Reactions (6)]
5
WARNING
S AND PRECAUTIONS
5.1 Concomitant
Gastric Malignancy
Symptomatic response to therapy with omeprazole does
not preclude the
presence of
gastric malignancy.
5.2 At
rophic gastritis
Atrophic gastritis has been noted occasionally in gastric corpus biopsies
from
patients treated long-term
with
omeprazole.
5.3
Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in patients taking PPIs including
ZEGERID.
Acute interstitial nephritis may occur at any point during PPI therapy and is
generally attributed to an idiopathic hypersensitivity reaction. Discontinue ZEGERID if
acute interstitial nephritis develops. [SeeContraindications (4)].
5.4 Cyanocobalam
in (vitamin B-12)
Deficiency
Daily treatment with any acid-suppressing medications
over a long period of
time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin
(vitamin B-12) caused by hypo-
or achlorhydria. Rare reports of
cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis
should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
5.5
Buffer Content
Each ZEGERID Capsule contains 1100 mg (13 mEq)
of sodium bicarbonate.
The total content of
sodium in each capsule is 304 mg.
Each packet of
ZEGERID Powder for Oral Suspension contains 1680 mg
(20 mEq) of
sodium bicarbonate (equivalent to 460 mg of Na+).
The sodium content of ZEGERID products should be taken into consideration when administering to patients
on
a sodium
restricted diet.
Because ZEGERID products contain sodium bicarbonate, they should be used with caution in patients
with Bartter’s syndrome, hypokalemia,
hypocalcemia, and problems with acid-base balance. Long-term
administration of bicarbonate with calcium or
milk can cause milk-alkali
syndrome.
Chronic use of sodium bicarbonate may lead to systemic alkalosis and increased sodium intake can produce edema and weight increase.
5.6 Clostridium
difficileAssociated Diarrhea
Published observational studies suggest that PPI therapy like ZEGERID may
be
associated with an increased risk of Clostridium difficileassociated diarrhea, especially in hospitalized patients. This diagnosis should be
considered for diarrhea that does not improve. [See Adverse Reactions
(6.2)]
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
5.7 Int
eraction with Clopidogrel
Avoid concomitant use of ZEGERID with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is
entirely due to an active metabolite. The metabolism
of
clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that
interfere with CYP2C19 activity. Concomitant use of
clopidogrel with 80 mg omeprazole reduces the pharmacological
activity of clopidogrel, even when administered 12 hours apart. When using ZEGERID, consider
alternative
anti-platelet therapy. [See Drug Interactions (7.5) and Pharmacokinetics (12.3)]
5.8
Bone Fracture
Several published observational studies
suggest that proton pump inhibitor
(PPI) therapy may be associated with an increased risk for osteoporosis-
related fractures of
the
hip, wrist, or spine.
The risk of
fracture was
increased in patients who received high-dose, defined as multiple daily doses, and long- term PPI therapy (a year
or longer). Patients should use the lowest dose and shortest duration of
PPI
therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures
should be managed according to the established treatment guidelines. [See Dosage and Administration (2) and Adverse Reactions (6.2)]
5.9 Hypomagn
esemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases
after
a year of therapy. Serious
adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium
replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or
who take PPIs with
medications
such as digoxin or drugs that may cause hypomagnesemia (e.g.,
diuretics), health care professionals may consider
monitoring magnesium levels
prior to initiation of
PPI treatment and periodically.[See Adverse Reactions (6.2)]
5.10 Concom
itant Use of ZEGERID with St
John’s Wort or Rifampin
Drugs which induce CYP2C19 OR CYP34A (such as St John’s
Wort or rifampin) can substantially decrease omeprazole concentrations [See Drug Interactions
(7.2)].Avoid concomitant use of ZEGERID with St John’s
Wort or
rifampin.
5.11 Int
eractions with
Investigations for Neuroendocrine Tumors
Serum chromogranin A (CgA)
levels increase secondary to drug-induced
decreases
in gastric acidity. The increased CgA level may cause false positive
results in diagnostic investigations
for
neuroendocrine tumors. Providers should temporarily stop omeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels
are
high. If
serial tests
are performed (e.g. for
monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. [See Pharmacodynamics (12.2)].
5.12 Concom
itant Use of ZEGERID with Methotrexate
Literature suggests that concomitant use of
PPIs with methotrexate (primarily
at high dose; see methotrexate prescribing information)
may
elevate and prolong serum levels
of methotrexate and/or its
metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a
temporary withdrawal of the PPI may be considered in some patients. [SeeDrug Interactions (7.8)].
6
ADV
ERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under
widely varying conditions,
adverse reaction rates observed in the clinical trials
of a
drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates
observed in clinical practice.
In the U.S. clinical trial population of 465 patients, the adverse reactions
summarized in Table 2 were reported to occur in 1% or more of
patients on therapy with omeprazole. Numbers in parentheses
indicate percentages of
the
adverse reactions considered by investigators
as possibly, probably or
definitely related to the drug.
|
|
Omeprazole (n
= 465)
|
Placebo (n = 64)
|
Ranitidine (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)
|
|
|
Table 2: Adverse Reactions Occurring In 1% or More of Patients on Omeprazole Therapy
BackPain 1.1 0.0 0.5 Table 3 summarizes the adverse reactions that occurred in 1% or
more of
omeprazole-treated patients from
international double-blind, and open-label clinical trials in which 2,631 patients and subjects received omeprazole.
Table 3: Incidence of Adverse Reactions ≥ 1% Table 4: Number (%)
of Critically Ill Patients with Causal Relationship not Assessed Frequently Occurring (≥ 3%) Adverse Events by Body
System and
Preferred Term
|
ZEGERID®
|
Cimetidine
|
|
|
(N=178)
|
(N=181)
|
|
MedDRA
|
|
Body System
|
All AEs
|
All AEs
|
|
PreferredTerm
|
n(%)
|
n(%)
|
|
BLOOD AND LYMPHATIC SYSTEM
|
|
DISORDERS
|
|
Anemia NOS
|
14 (7.9)
|
14 (7.7)
|
|
Anemia NOS Aggravated
|
4 (2.2)
|
7 (3.9)
|
|
Thrombocytopenia
|
18(10.1)
|
11(6.1)
|
|
CARDIAC DISORDERS
|
|
Atrial Fibrillation
|
11 (6.2)
|
7 (3.9)
|
|
Bradycardia NOS
|
7 (3.9)
|
5 (2.8)
|
|
Supraventricular Tachycardia
|
6 (3.4)
|
2 (1.1)
|
|
Tachycardia NOS
|
6 (3.4)
|
6 (3.3)
|
|
VentricularTachycardia
|
8(4.5)
|
6(3.3)
|
|
GASTROINTESTINAL DISORDERS *
|
|
Constipation
|
8 (4.5)
|
8 (4.4)
|
|
Diarrhea NOS
|
7 (3.9)
|
15 (8.3)
|
|
GastricHypomotility
|
3(1.7)
|
6(3.3)
|
|
GENERAL DISORDERS AND
|
|
ADMINISTRATION SITE CONDITIONS
|
|
Hyperpyrexia
|
8 (4.5)
|
3 (1.7)
|
|
Edema NOS
|
5 (2.8)
|
11 (6.1)
|
|
Pyrexia
|
36 (20.2)
|
29 (16.0)
|
|
INFECTIONS AND INFESTATIONS
|
|
Candidal Infection NOS
|
3 (1.7)
|
7 (3.9)
|
|
Oral Candidiasis
|
7 (3.9)
|
1 (0.6)
|
|
Sepsis NOS
|
9 (5.1)
|
9 (5.0)
|
|
Urinary Tract Infection NOS
|
4 (2.2)
|
6 (3.3)
|
|
INVESTIGATIONS
|
|
Liver Function Tests NOS Abnormal
|
3 (1.7)
|
6 (3.3)
|
|
METABOLISM AND NUTRITION
|
|
DISORDERS
|
|
Fluid Overload
|
9 (5.1)
|
14 (7.7)
|
|
Hyperglycaemia NOS
|
19 (10.7)
|
21 (11.6)
|
|
Hyperkalaemia
|
4 (2.2)
|
6 (3.3)
|
|
Hypernatraemia
|
3 (1.7)
|
9 (5.0)
|
|
Hypocalcaemia
|
11 (6.2)
|
10 (5.5)
|
|
Hypoglycaemia NOS
|
6 (3.4)
|
8 (4.4)
|
|
Hypokalaemia
|
22 (12.4)
|
24 (13.3)
|
|
Hypomagnesaemia
|
18 (10.1)
|
18 (9.9)
|
|
Hyponatraemia
|
7 (3.9)
|
5 (2.8)
|
|
Hypophosphataemia
|
11 (6.2)
|
7 (3.9)
|
|
PSYCHIATRIC DISORDERS
|
|
Agitation
|
6 (3.4)
|
16 (8.8)
|
|
RESPIRATORY, THORACIC AND
|
|
MEDIASTINAL DISORDERS
|
|
Acute Respiratory Distress Syndrome
|
6 (3.4)
|
7 (3.9)
|
|
Nosocomial Pneumonia
|
20 (11.2)
|
17 (9.4)
|
|
Pneumothorax NOS
|
1 (0.6)
|
8 (4.4)
|
|
Respiratory Failure
|
3 (1.7)
|
6 (3.3)
|
|
SKIN AND SUBCUTANEOUS
TISSUE
|
|
DISORDERS
|
|
Decubitus Ulcer
|
6 (3.4)
|
5 (2.8)
|
|
Rash NOS
|
10 (5.6)
|
11 (6.1)
|
|
VASCULAR DISORDERS
|
|
Hypertension NOS
|
14 (7.9)
|
6 (3.3)
|
|
HypotensionNOS
|
17(9.6)
|
12(6.6)
|
|
|
Omeprazole Placebo
(n = 2631) (n = 120)
|
Abdominal pain
|
5.2
|
3.3
|
|
Asthenia
|
1.3
|
0.8
|
|
Digestive System
|
|
|
Body as
a Whole, site unspecified
|
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
|
NervousSystem/Psychiatric Headache 2.9
2.5
A controlled clinical trial was
conducted in 359 critically ill patients, comparing ZEGERID 40 mg/1680 mg suspension once daily to I.V.
cimetidine 1200 mg/day for
up
to 14 days. The incidence and total number of AEs
experienced by ≥ 3% of patients in either group are presented in Table 4
by
body system and preferred term.
* Clinically significant upper
gastrointestinal bleeding was
considered a
serious adverse event but it is not included in this table.
NOS = Not otherwise specified.
6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of omeprazole. Because these reactions
are
voluntarily reported from
a
population of uncertain size, it is not always possible to reliably estimate their
actual frequency or establish a causal relationship to drug exposure.
Body as a Whole:Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise.
Cardiovascular:Chest pain or angina, tachycardia, bradycardia, palpitation,
elevated blood pressure, and peripheral edema.
Gastrointestinal:Pancreatitis
(some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of
the tongue, dry mouth, stomatitis and abdominal swelling. 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. Gastroduodenal carcinoids have been reported in patients with Zollinger-
Ellison syndrome on long-term treatment with omeprazole. This
finding is
believed to be a manifestation of the underlying condition, which is known to
be
associated with such tumors.
Hepatic:Mild and, rarely, marked elevations of liver function tests [ALT
(SGPT), AST (SGOT), γ-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.
Infections and Infestations:
Clostridium difficileassociated diarrhea.
Metabolism and Nutritional Disorders:Hyponatremia, hypoglycemia,
hypomagnesemia, and weight gain.
Musculoskeletal:Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.
Nervous System/Psychiatric:Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.
Respiratory:Epistaxis, pharyngeal pain.
Skin:Severe generalized skin reactions
including toxic epidermal necrolysis
(TEN; some fatal), Stevens-Johnson syndrome, and erythema multiforme (some severe); purpura and/or
petechiae (some with rechallenge); skin
inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.
Special Senses:Tinnitus, taste perversion.
Ocular:Blurred vision, ocular irritation, dry eye syndrome, optic atrophy,
anterior
ischemic optic neuropathy, optic neuritis and double vision.
Urogenital:Interstitial nephritis
(some with positive rechallenge), urinary
tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and
gynecomastia.
Hematologic:Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, 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.
Additional adverse reactions that could be caused by sodium bicarbonate include metabolic alkalosis, seizures, and tetany.
7
DRU
G INTERACTIONS
7.1 Drugs for Which Gastric pH Can Affect Bioavailability
Due to its effects
on
gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is
an
important determinant of their bioavailability.
Like with other
drugs that decrease the intragastric acidity, the absorption of
drugs
such as ketoconazole, atazanavir, iron salts, erlotinib,
and
mycophenolate mofetil (MMF) can decrease, while the absorption of
drugs
such as digoxin can increase during treatment with omeprazole.
Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy
subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Coadministration of digoxin with ZEGERID is expected to increase the systemic exposure of digoxin. Therefore, patients
may
need to be
monitored when digoxin is taken concomitantly with ZEGERID.
Co-administration of
omeprazole in healthy subjects and in transplant patients
receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF
solubility at an increased gastric pH. The clinical relevance of
reduced MPA exposure on organ rejection has not been established in transplant patients
receiving ZEGERID and MMF. Use ZEGERID with caution in transplant patients
receiving MMF. [See Clinical Pharmacology (12.3)]
7.2 D
rugs
Metabolized by Cytochrome P450 (CYP)
Omeprazole can prolong the elimination of
diazepam, warfarin and
phenytoin, drugs that are metabolized by oxidation in the liver. There have
been reports
of increased INR and prothrombin time in patients
receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly.
Increases
in INR and prothrombin time may lead to abnormal bleeding and
even death. Patients
treated with proton pump inhibitors and warfarin may need to be monitored for
increases in INR and prothrombin time.
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., cyclosporine, disulfiram, benzodiazepines). Patients
should be monitored to determine if it is necessary
to adjust the dosage of
these drugs when taken concomitantly with
ZEGERID.
Concomitant administration of
omeprazole and voriconazole (a combined
inhibitor
of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of
omeprazole is not normally
required. When voriconazole (400 mg every 12 hours
for
one day, then 200
mg
for 6 days) was
given with omeprazole (40 mg once daily for
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.
Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male
subjects, St John’s wort (300 mg three times daily for
14
days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor
metabolisers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or
rifampin with omeprazole.
7.3 Ant
iretroviral Agents
Concomitant administration of
atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and
thereby reduce its therapeutic effect.
Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms
behind these interactions are not always known. Increased gastric pH during omeprazole treatment may
change the absorption of the antiretroviral drug. Other
possible interaction
mechanisms are via CYP2C19. For
some antiretroviral drugs, such as
atazanavir and nelfinavir, decreased serum
levels have been reported when
given together with omeprazole. Following multiple doses of
nelfinavir (1250 mg, twice daily)
and
omeprazole (40 mg, daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively
for nelfinavir
and M8. Following multiple doses
of atazanavir (400 mg, daily)
and
omeprazole (40 mg, daily, 2 hours
before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.
Increased Concentration of Saquinavir
For other
antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in Cmax by 75% and in Cmin by 106% following multiple dosing of
saquinavir/ritonavir (1000/100
mg)
twice daily for
15
days with omeprazole 40 mg daily co-administered days 11 to 15. Dose reduction of saquinavir should be considered from the
safety perspective for
individual patients. There are also some antiretroviral
drugs
of which unchanged serum levels have been reported when given with omeprazole.
7.4 Comb
ination Therapy with Clarithromycin
Concomitant administration of clarithromycin with other drugs can lead to
serious adverse reactions due to drug interaction [See Warnings and Precautionsin prescribing information for
clarithromycin]. Because of
these
drug interactions, clarithromycin is contraindicated for
co-administration with
certain drugs. [SeeContraindicationsin prescribing information for
clarithromycin]
7.5 C
lopidogrel
Omeprazole is an
inhibitor of
CYP2C19 enzyme. Clopidogrel is
metabolized
to its active metabolite in part by CYP2C19. Concomitant use of
omeprazole
80 mg results in reduced plasma concentrations
of
the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of
ZEGERID with clopidogrel. When using ZEGERID,
consider
use of
alternative anti-platelet therapy. [See Pharmacokinetics
(12.3)]
7.6
Tacrolimus
Concomitant administration of
omeprazole and tacrolimus may increase the serum levels
of tacrolimus.
7.7 Int
eractions With Investigations of
Neuroendocrine Tumors
Drug-induced decrease in gastric acidity results
in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. [See Clinical Pharmacology (12)].
7.8 M
ethotrexate
Case reports, published population pharmacokinetic studies, and retrospective analyses
suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum
levels
of methotrexate and/or its metabolite
hydroxymethotrexate. However, no formal drug interaction studies of
methotrexate with PPIs have been conducted. [See Warnings and Precautions
(5.12)].
8
US
E IN SPECIFIC POPULATIONS
8.1 Pregnancy Pregnancy Category CRiskSummary
There are no adequate and well-controlled studies
on
the use of
ZEGERID in pregnant women. Available epidemiologic data fail to demonstrate an
increased risk of
major congenital malformations
or other
adverse pregnancy outcomes
with
first trimester
omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of
oral
esomeprazole magnesium
in
rats and rabbits with doses about68 times and 42 times, respectively, an oral human dose of
40
mg (based on a body surface
area basis
for
a 60 kg person). However, changes
in
bone morphology were
observed in offspring of
rats dosed through most of
pregnancy and lactation
at doses
equal to or
greater
than approximately 33.6 times
an
oral human dose of
40
mg (see Animal Data). Because of
the
observed effect at high doses
of esomeprazole magnesium on developing bone in rat studies, ZEGERID should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Human Data
Four published epidemiological studies
compared the frequency of
congenital abnormalities
among infants born to women who used omeprazole during pregnancy with the frequency of
abnormalities
among infants of women exposed to H2-receptor antagonists or other
controls.
A population-based retrospective cohort epidemiological study from
the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants
(824 exposed during the first trimester with 39 of
these exposed beyond first trimester, and 131
exposed after
the
first trimester)
whose mothers used omeprazole during
pregnancy. The number
of infants
exposed in uteroto omeprazole that had any malformation, low birth weight, low Apgar
score, or
hospitalization was
similar to the number observed in this population. The number of
infants born with ventricular septal defects
and
the number
of stillborn infants was
slightly higher
in the omeprazole-exposed infants
than
the expected number in this population.
A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers
used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers
did
not use any proton pump inhibitor. The overall rate of birth defects
in
infants born to mothers with first trimester
exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor
during the first trimester.
A retrospective cohort study reported on 689 pregnant women exposed to
either
H2-blockers
or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with
first trimester exposure to omeprazole, an H2-blocker, or
were unexposed was 3.6%, 5.5%, and 4.1% respectively.
A small prospective observational cohort study followed 113 women exposed
to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was
4%
in the omeprazole
group, 2% in controls
exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of
spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the
groups.
Several studies
have reported no apparent adverse short-term
effects
on
the infant when single dose oral or intravenous
omeprazole was
administered to over
200
pregnant women as premedication for cesarean section under
general anesthesia.
AnimalData
Reproductive studies conducted with omeprazole in rats at oral doses up to
138 mg/kg/day (about 33.6 times
an
oral human dose of 40 mg on a body
surface area basis)
and
in rabbits at doses up to 69 mg/kg/day (about 33.6times an oral human dose of 40 mg on a body surface area basis) 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 (about 3.36 to 33.6
times
an
oral human dose of 40 mg on a body surface area basis) 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 at 13.8 to 138.0 mg/kg/day (about 3.36 to 33.6 times
an oral human dose of
40
mg on a body surface area basis).
Reproduction studies have been performed with esomeprazole magnesium in
rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits
at
oral doses
up
to 86 mg/kg/day (about42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or
harm
to the fetus
due to esomeprazole magnesium.
A pre- and postnatal developmental toxicity study in rats with additional
endpoints to evaluate bone development were performed with the S-
enantiomer, esomeprazole magnesium
at oral doses
of 14 to 280 mg/kg/day
(about 3.4 to 68 times
an
oral human dose of
40
mg of esomeprazole on a
body surface area basis). Neonatal/early postnatal (birth to weaning)
survival was decreased at doses
equal to or greater than 138 mg/kg/day (about
33.6 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or
general
developmental delays
in the immediate post-weaning timeframe were evident
at doses equal to or greater than 69 mg /kg/day (about 16.8 times
an
oral human dose of
40
mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness
of
the tibial growth plate and minimal to mild bone marrow hypocellularity were
noted at doses of
esomeprazole magnesium
equal to or greater than 14 mg/kg/day (about 3.4 times
an
oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur
was observed in offspring of rats treated with oral doses
of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis).
Effects
on
maternal bone were observed in pregnant and lactating rats
in
a pre- and postnatal toxicity study when esomeprazole magnesium
was administered at oral doses of
14
to 280 mg/kg/day (about 3.4 to 68 times an
oral human dose of 40 mg on a body surface area basis). When rats
were dosed from
gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as
compared to placebo treatment) was
observed at doses
of esomeprazole magnesium equal to or
greater
than 138 mg/kg/day (about 33.6 times
an oral human dose of
40
mg on a body surface area basis).
A pre-
and
post natal development study in rats
with esomeprazole strontium
(using equimolar doses compared to esomeprazole magnesium
study)
produced similar results in dams and pups as described above.
8.3 Nu
rsing Mothers
Omeprazole concentrations have been measured in breast milk of a woman following oral administration of
20
mg. The peak concentration of
omeprazole in breast milk was less than 7% of
the peak serum concentration.
The concentration will correspond to 0.004 mg of
omeprazole in 200 mL of milk. Because omeprazole is excreted in human milk, because of the potential
for
serious adverse reactions in nursing infants
from
omeprazole, and because of
the
potential for
tumorigenicity shown for omeprazole in rat
carcinogenicity studies, a decision should be made to discontinue nursing or
to discontinue the drug, taking into account the importance of
the
drug to the mother. In addition, sodium bicarbonate should be used with caution in nursing mothers.
8.4
Pediatric Use
Safety and effectiveness
of ZEGERID have not been established in pediatric patients
less
than
18 years
of age.
JuvenileAnimalData
In a juvenile rat toxicity study, esomeprazole was
administered with both
magnesium
and
strontium salts at oral doses about 34 to 68 times
a daily
human dose of 40 mg on a body surface area basis. Increases
in death were
seen at the high dose, and at all doses of
esomeprazole, there were decreases
in body weight, body weight gain, femur
weight and femur length, and decreases in overall growth. [See Nonclinical Toxicology (13.2)]
8.5 G
eriatric Use
Omeprazole was
administered to over 2000 elderly individuals (≥ 65 years of
age) in clinical
trials in the U.S. and Europe. There were no differences
in safety and effectiveness
between the elderly and younger
subjects. Other reported clinical experience has not identified differences
in response
between the elderly and younger
subjects, but greater sensitivity of some
older individuals cannot be ruled out.
Pharmacokinetic studies
with
buffered omeprazole have shown the
elimination rate was
somewhat decreased in the elderly and bioavailability was
increased. The plasma clearance of omeprazole was 250 mL/min (about half that of
young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking ZEGERID. However, no
dosage adjustment is necessary in the elderly. [See Clinical Pharmacology
(12.3)]
8.6 H
epatic Impairment
Consider dose reduction, particularly for maintenance of healing of erosive esophagitis.[See Clinical Pharmacology (12.3)]
8.7 R
enal Impairment
No dose reduction is necessary.[See Clinical Pharmacology (12.3)]
8.8 As
ian Population
Recommend dose reduction, particularly for
maintenance of
healing of
erosive esophagitis.[See Clinical Pharmacology (12.3)]
10 OV
ERDOSAGE
Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose).
Manifestations
were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry
mouth, and other adverse reactions similar to those seen in normal clinical experience [See Adverse Reactions (6)].Symptoms were transient, and no
serious clinical outcome has been reported when omeprazole was taken alone. 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.
As with the management of
any
overdose, the possibility of
multiple drug
ingestion should be considered. For current information on treatment of any
drug overdose, a certified Regional Poison Control Center should be
contacted. Telephone numbers are listed in the Physicians’
Desk Reference
(PDR) or local telephone book.
Single oral doses
of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals
given these doses
showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration.
In addition, a sodium bicarbonate overdose may cause hypocalcemia, hypokalemia, hypernatremia, and seizures.
11 D
ESCRIPTION
ZEGERID® (omeprazole/sodium bicarbonate)
is a
combination of omeprazole, a proton-pump inhibitor, and sodium bicarbonate, an antacid.
Omeprazole is
a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-
dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, a racemic mixture of
two
enantiomers
that inhibits gastric acid secretion. Its empirical
formula is
C17H19N3O3S, with a molecular
weight of
345.42. The structural formula is:
Omeprazole is a white to off-white crystalline powder
which melts with decomposition at about 155°C. 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.
ZEGERID is supplied as immediate-release capsules
and
unit-dose packets as powder
for
oral suspension. Each capsule contains either 40 mg or 20 mg of omeprazole and 1100 mg of sodium bicarbonate with the following
excipients: croscarmellose sodium and sodium
stearyl fumarate. Packets
of powder
for
oral suspension contain either 40 mg or
20
mg of omeprazole and 1680 mg of sodium bicarbonate with the following excipients: xylitol, sucrose, sucralose, xanthan gum, and flavorings.
12 C
LINICAL PHARMACOLOGY
12.1 Mechanism of
Action
Omeprazole belongs to a 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.
Omeprazole is
acid
labile and thus rapidly degraded by gastric acid. ZEGERID Capsules and Powder
for Oral Suspension are immediate-release
formulations that contain sodium bicarbonate which raises the gastric pH and thus protects
omeprazole from
acid
degradation.
12.2
Pharmacodynamics
Antisecretory Activity
Results from a PK/PD study of
the
antisecretory effect of repeated once-daily
dosing of 40 mg and 20 mg of
ZEGERID Oral Suspension in healthy subjects are shown in Table 5 below.
Table 5: Effect of ZEGERID Oral Suspension on Intragastric pH, Day 7
Omeprazole/Sodium
Bicarbonate
40
mg/1680 20 mg/1680
mg mg
Parameter (n=24) (n=28)
% Decrease from
Baseline for Integrated 84% 82%
Gastric Acidity (mmol⋅hr/L)
Coefficient of variation 20% 24%
% Time Gastric pH > 4* 77% 51%
(Hours)* (18.6 h) (12.2 h)
Coefficient of variation 27% 43%
Median pH 5.2 4.2
Coefficient of
variation 17% 37%
Note: Values represent medians. All parameters
were measured over a 24-hour period.
* p < 0.05 20 mg vs. 40 mg
Results
from
a separate PK/PD study of antisecretory effect on repeated once-daily dosing of 40 mg/1100 mg and 20 mg/1100 mg of ZEGERID Capsules
in
healthy subjects show similar effects
in general on the above
three PD parameters
as those for
ZEGERID 40 mg/1680 mg and
20 mg/1680 mg Oral Suspension, respectively.
The antisecretory effect lasts
longer than would be expected from the very short (1 hour)
plasma half-life, apparently due to irreversible binding to the
parietal H+/K+ ATPase enzyme.
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 Nonclinical Toxicology (13.1)]. Carcinoid tumors have also been observed in rats
subjected to fundectomy or long-term treatment with other
proton pump inhibitors
or high doses
of H2-receptor
antagonists. Human gastric biopsy specimens have been obtained from
more than 3000 patients treated with omeprazole in long-term
clinical trials. The incidence of
ECL
cell hyperplasia in these studies
increased with time; however, no case of
ECL cell carcinoids, dysplasia, or
neoplasia has been
found in these patients. These studies are of
insufficient duration and size to
rule out the possible influence of
long-term administration of omeprazole on the development of
any premalignant or malignant conditions.
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.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased
serum
Chromogranin A (CgA) levels. The increased CgA levels
may
cause false positive results
in
diagnostic investigations
for
neuroendocrine tumors.
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
secretin.
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 I.V. 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.
The course of
Barrett’s esophagus in 106 patients was
evaluated in a U.S.
double-blind controlled study of
omeprazole 40 mg b.i.d. for
12
months
followed by 20 mg b.i.d. for 12 months or
ranitidine 300 mg b.i.d. for
24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during
antisecretory therapy, complete elimination of
Barrett’s mucosa was not
achieved. No significant difference was observed between treatment groups in development of
dysplasia in Barrett’s
mucosa and no patient developed
esophageal carcinoma during treatment. No significant differences
between treatment groups
were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter.
12.3
Pharmacokinetics
Absorption
In separate in vivobioavailability studies, when ZEGERID Oral Suspension
and
Capsules
are
administered on an empty stomach 1 hour prior to a meal,
the
absorption of
omeprazole is rapid, with mean peak plasma levels (% CV)
of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL (49%),
respectively, and time to peak of approximately 30 minutes
(range 10-90 min)
after
a single-dose or
repeated-dose administration. Absolute bioavailability
of ZEGERID Powder
for
Oral Suspension (compared to I.V. administration)
is about 30-40% at doses
of 20 – 40 mg, due in large part to presystemic
metabolism.
When ZEGERID Oral
Suspension 40 mg/1680 mg was administered in a
two-dose loading regimen, the omeprazole AUC (0-inf) (ng⋅hr/mL) was 1665
after
Dose 1 and 3356 after Dose 2, while Tmax was approximately 30 minutes for both Dose 1 and Dose 2.
Following single or repeated once daily dosing, peak plasma concentrations of
omeprazole from ZEGERID are approximately proportional from 20 to 40 mg doses, but a greater
than linear mean AUC (three-fold increase)
is
observed when doubling the dose to 40 mg. The bioavailability of omeprazole from ZEGERID increases
upon repeated administration.
When ZEGERID is administered 1 hour
after
a meal, the omeprazole AUC is reduced by approximately 24% relative to administration 1 hour prior to a
meal.
Distribution
Omeprazole is
bound to plasma proteins. Protein binding is approximately 95%.
Metabolism
Following single-dose oral administration of omeprazole, the majority of
the dose (about 77%) is eliminated in urine as at
least six metabolites. Two
metabolites have been 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.
Excretion
Following single-dose oral administration of omeprazole, little if
any, unchanged drug is excreted in urine. The mean plasma omeprazole half-life in healthy subjects is approximately 1 hour (range 0.4 to 3.2 hours)
and
the total body clearance is 500-600 mL/min.
Concom
itant Use with Clopidogrel
In a crossover
clinical study, 72 healthy subjects were administered
clopidogrel (300 mg loading dose followed by 75 mg per
day)
alone and with omeprazole (80 mg at the same time as
clopidogrel) for 5 days. The exposure to the active metabolite of
clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together.
Results
from
another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading
dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for
30
days. Exposure to the active metabolite of clopidogrel was
reduced by 41% to 46% over
this
time period.
In another study, 72 healthy subjects were given the same doses of
clopidogrel and 80 mg omeprazole but the drugs
were administered 12 hours
apart; the results
were similar, indicating that administering clopidogrel and
omeprazole at different times
does
not prevent their interaction.
Concom
itant Use with Mycophenolate Mofetil
Administration of
omeprazole 20 mg twice daily for
4 days and a single 1000 mg dose of
MMF 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
MPA.
Sp
ecial Populations
Geriatric
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 subjects, versus 58% in young subjects
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 subjects) and its plasma half-life
averaged one hour, similar to that of
young healthy subjects.
Pediatric
The pharmacokinetics of
ZEGERID has not been studied in patients < 18 years of
age.
Gender
There are no known differences in the absorption or excretion of omeprazole between males
and
females.
Hepatic Insufficiency
In patients with chronic hepatic disease, the bioavailability of
omeprazole
from
a buffered solution increased to approximately 100% compared to an
I.V. dose, reflecting decreased first-pass
effect, and the mean plasma half-life
of the drug increased to nearly 3 hours
compared to the mean half-life of
1
hour in normal subjects. Plasma clearance averaged 70 mL/min, compared to
a value of 500-600 mL/min in normal subjects. Dose reduction, particularly
where maintenance of
healing of
erosive esophagitis is indicated, for
the
hepatically impaired should be considered.
Renal Insufficiency
In patients with chronic renal impairment, whose creatinine clearance ranged
between 10 and 62
mL/min/1.73 m2, the disposition of omeprazole from
a buffered solution was
very similar
to that in healthy subjects, 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.
Asian Population
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 Asian subjects should be considered.
13 NONC
LINICAL TOXICOLOGY
13.1 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 0.4 to 34.2 times the
human dose of 40 mg/day on a body surface area basis) 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 3.36 times the
human dose of 40 mg/day on a body surface area basis)
for
one year, then followed for
an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of
treatment-related ECL cell hyperplasia was observed
at the end of one year
(94% treated versus 10% controls). By the second year
the
difference between treated and control rats
was much smaller
(46% versus
26%) but still showed more hyperplasia in the treated group. Gastric
adenocarcinoma 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. In a 52-week toxicity study in Sprague-Dawley rats, brain
astrocytomas
were found in a small number
of males that received omeprazole at dose levels of
0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day on a body surface area basis). No astrocytomas
were observed in female rats in this study. In a 2-year
carcinogenicity study in Sprague-Dawley rats, no astrocytomas
were found in males and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of
40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity
equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.
14 C
LINICAL STUDIES
14.1 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 and 4 weeks was
significantly higher with omeprazole 20 mg once a day than with placebo (p ≤ 0.01). (See Table 6)
Table 6: Treatment
of Active Duodenal Ulcer
%
of Patients Healed
Omeprazole Placebo
20 mg a.m. a.m.
(n=99) (n=48)
Week 2 41* 13
Week4 75* 27
* (p ≤ 0.01)
Complete daytime and nighttime pain relief occurred significantly faster
(p
≤ 0.01) in patients
treated with omeprazole 20 mg than in patients treated with
placebo. At the end of
the study, significantly more patients
who had received
omeprazole had complete relief
of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 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
omeprazole 20 mg once a day than
with
ranitidine 150 mg b.i.d. (p < 0.01). (See Table 7)
Table 7: Treatment
of Active Duodenal Ulcer % of Patients Healed
|
Omeprazole 20 mg a.m.
|
Ranitidine 150 mg b.i.d.
|
|
(n
= 145)
|
(n
= 148)
|
|
Week 2
|
42
|
34
|
|
Week 4
|
82*
|
63
|
|
|
study of
omeprazole did not show increased tumor
occurrence, but the study
was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity
study was not positive.
Omeprazole was positive for
clastogenic effects in an in vitrohuman lymphocyte chromosomal aberration assay, in one of two in vivomouse
micronucleus tests, and in an in vivobone marrow cell chromosomal
aberration assay. Omeprazole was negative in the in vitroAmes Test, an invitromouse lymphoma cell forward mutation assay and an in vivorat liver DNA damage assay.
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 Warnings and Precautions (5)]. Carcinoid tumors have also been observed in rats subjected to fundectomy or
long-term
treatment with other proton pump inhibitors
or high doses
of H2-receptor antagonists.
Omeprazole at oral doses up to 138 mg/kg/day (about 33.6 times
the human dose of
40
mg/day on a body surface area basis)
was found to have no effect
on
the fertility and general reproductive performance in rats.
13
.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Reproduction studies conducted in pregnant rats with omeprazole at doses up
to 138 mg/kg/day (about 33.6times an oral human dose of
40
mg on a body surface area basis) and in pregnant rabbits at doses
up
to 69 mg/kg/day (about 33.6times an oral human dose of 40 mg on a body surface area basis) did not
disclose any evidence for a teratogenic potential of
omeprazole.
In rabbits, omeprazole in a dose range of
6.9 to 69 mg/kg/day (about 3.3 to
33.6 times the human dose of
40 mg/day on a body surface area basis) 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 at 13.8 to 138.0 mg/kg/day (about 3.3 to 33.6 times the human dose of 40 mg/day on a body surface area basis).
JuvenileAnimalStudy
A 28-day toxicity
study with a 14-day recovery phase was conducted in
juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface
area basis). An increase in the number of deaths at the high dose of 280 mg
/kg/day was observed when juvenile rats were administered esomeprazole
ReferencmeagInDes:iu3m6f7ro5m79po8stnatal day 7 through postnatal day 35.
In addition, doses
* (p < 0.01)
Healing occurred significantly faster in patients treated with omeprazole 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, 40 mg and 20 mg of omeprazole were compared to 150
mg
b.i.d. of
ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses
of omeprazole were statistically superior
(per protocol)
to ranitidine, but 40 mg was not superior to 20 mg of
omeprazole, and at 8 weeks there was
no
significant difference between any of the active drugs. (See Table 8)
Table8: TreatmentofActiveDuodenalUlcer%ofPatientsHealed
Omeprazole Ranitidine
40
mg 20 mg 150 mg b.i.d.
(n = 36) (n = 34) (n = 35)
Week 2 83* 83* 53
Week 4 100* 97* 82
Week8 100 100 94
*(p ≤ 0.01)
14.2
Gastr
ic 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. (See Table 9)
Table 9: Treatment of
Gastric Ulcer % of
Patients Healed (All Patients
Treated)
Omeprazole Omeprazole Placebo 40 mg q.d. 20 mg q.d. (n = 104)
(n=214) (n=202)
Week 4 55.6** 47.5** 30.8
Week 8 82.7**,+ 74.8** 48.1
** (p < 0.01)
Omeprazole 40 mg or 20 mg versus placebo
+ (p < 0.05) Omeprazole 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 effective than 20 mg at 8 weeks.
In a foreign, multinational, double-blind study of
602
patients 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. (See Table 10)
|
Omeprazole 40 mg q.d.
|
Omeprazole 20 mg q.d.
|
Ranitidine 150 mg b.i.d.
|
|
(n=187)
|
(n=200)
|
(n=199)
|
|
Week 4
|
78.1**,++
|
63.5
|
56.3
|
|
Week 8
|
91.4**,++
|
81.5
|
78.4
|
|
|
Table 10: Treatment
of Gastric Ulcer % of Patients
Healed
(All Patients
Treated)
Table 13: Life Table Analysis
Omeprazole Omeprazole Placebo 20 mg q.d.
20 mg 3 days per week (n = 131)
(n=138) (n=137)
Percent in endoscopic 70* 34 11
remissionat6months
* (p < 0.01) Omeprazole 20 mg once daily versus
Omeprazole 20 mg 3
consecutive days per week or placebo.
In an international, multicenter, double-blind study, omeprazole 20 mg daily and 10 mg daily were compared to ranitidine 150 mg twice daily in patients
with
endoscopically confirmed healed esophagitis. Table 14 provides the results
of this
study for
maintenance of
healing of
erosive esophagitis.
|
Omeprazole
|
Omeprazole
|
Ranitidine
|
|
20 mg q.d.
|
10 mg q.d.
|
150 mg b.i.d.
|
|
(n
= 131)
|
(n
= 133)
|
(n
= 128)
|
|
Percent in
|
|
endoscopic
remission at 12
|
77*
|
58‡
|
46
|
|
months
|
|
|
|
|
|
|
|
Table 14: Life Table Analysis
**(p < 0.01)
Omeprazole 40 mg versus ranitidine
++(p < 0.01)
Omeprazole 40 mg versus 20 mg
14.3
Gastro
esophageal Reflux Disease (GERD)
Symptomatic GERD -A placebo controlled study was
conducted in Scandinavia to compare 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 in Table 11.
|
Omeprazole 20 mg a.m.
|
Omeprazole 10 mg a.m.
|
Placebo a.m.
|
|
All patients
Patients with confirmed
|
46*,†
(n = 205)
56*,†
|
31†
(n = 199)
36†
|
13
(n = 105)
14
|
|
GERD
|
(n = 115)
|
(n = 109)
|
(n = 59)
|
|
|
Table 11: % Successful Symptomatic Outcomea
a Defined as complete resolution of
heartburn
*
(p < 0.005) versus
10
mg
† (p < 0.005) versus
placebo
Erosive Esophagitis
-In a U.S. multicenter double-blind placebo controlled
study of 40 mg or 20 mg of
omeprazole 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
shown in Table 12.
|
Omeprazole
|
Omeprazole
|
|
|
40 mg
(n=87)
|
20 mg
(n=83)
|
Placebo
(n=43)
|
|
|
Table 12: % Patients Healed
Week 4 45* 39* 7
Week8 75* 74* 14
*
(p < 0.01) Omeprazole versus
placebo.
In this study, the 40-mg dose was
not superior to the 20-mg dose of omeprazole in the percentage healing rate. Other
controlled clinical trials
have also shown that omeprazole is effective in severe GERD. In
comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or
above, omeprazole in a dose of
20
mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients
treated with omeprazole than in those taking placebo or histamine H2-receptor antagonists.
In this and five other
controlled GERD studies, significantly more patients
taking 20 mg omeprazole (84%) reported complete relief
of GERD symptoms than patients receiving placebo (12%).
14.4
Long Term Maintenance Treatment of Erosive Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled study; two dose regimens of
omeprazole were studied in patients
with endoscopically confirmed healed esophagitis. Results to determine
ReferencmeainIDten:a3nc6e7o5f
7he9a8ling of
erosive esophagitis are shown in Table 13.
* (p = 0.01) Omeprazole 20 mg once daily versus
Omeprazole 10 mg once
daily or Ranitidine.
‡ (p = 0.03)
Omeprazole 10 mg once daily versus Ranitidine.
In patients who initially had grades
3 or
4 erosive esophagitis, for maintenance after healing 20 mg daily of omeprazole was effective, while
10
mg did not demonstrate effectiveness.
14.5
R
eduction of Risk of Upper Gastrointestinal Bleeding in
Critically Ill Patients
A double-blind, multicenter, randomized, non-inferiority clinical trial was conducted to compare ZEGERID Oral Suspension 40 mg/1680 mg and I.V.
cimetidine for
the reduction of risk of upper
gastrointestinal (GI) bleeding in
critically ill patients
(mean APACHE II score = 23.7). The primary endpoint was
significant upper GI bleeding defined as bright red blood which did not clear
after
adjustment of
the nasogastric tube and a 5 to 10 minute lavage, or
persistent Gastroccult® positive coffee grounds
for
8 consecutive hours
which did not clear with 100 cc lavage. ZEGERID Oral
Suspension
40 mg/1680 mg (two doses
administered 6 to 8 hours
apart on the first day
via
orogastric or
nasogastric tube, followed by 40 mg q.d. thereafter) was
compared to continuous
I.V. cimetidine (300 mg bolus, and 50 to 100 mg/hr continuously thereafter)
for
up
to 14 days
(mean = 6.8 days). A total of
359 patients
were studied, age range 16 to 91 (mean = 56 yrs), 58.5% were males, and 64% were Caucasians. The results
of the study showed that ZEGERID was
non-inferior
to I.V. cimetidine, 10/181(5.5%) patients in the
cimetidine group vs. 7/178 (3.9%) patients in the ZEGERID group
experienced clinically significant upper GI bleeding.
15 R
EFERENCES
1. Friedman JM and Polifka JE.
Omeprazole. In: Teratogenic Effects of
Drugs. A Resource for Clinicians (TERIS). 2nd ed. Baltimore, MD: The
Johns Hopkins University Press 2000; p. 516.
2. Kallen BAJ. Use of omeprazole during pregnancy – no hazard demonstrated in 955 infants exposed during pregnancy. Eur Obstet
Gynecol Reprod Biol2001; 96(1):63-8.
3. Ruigómez A, Rodriquez LUG, Cattaruzzi C, et al. Use of cimetidine, omeprazole, and ranitidine in pregnant women and pregnancy outcomes. Am J Epidemiol1999; 150: 476-81.
4. Lalkin A, Loebstein, Addis A, et al. The safety of omeprazole during
pregnancy: a multicenter
prospective controlled study. Am J Obstet Gynecol1998: 179:727-30.
16 HO
W SUPPLIED/STORAGE AND HANDLING
ZEGERID 20-mg Capsules: Each opaque, hard gelatin, white capsule, imprinted with the Santarus logo and “20”, contains 20 mg omeprazole and 1100 mg sodium bicarbonate.
NDC 68012-102-30 Bottles
of 30 capsules
ZEGERID 40-mg Capsules: Each opaque, hard gelatin, colored dark blue
and
white capsule, imprinted with the Santarus logo and “40”, contains 40 mg
omeprazole and 1100 mg sodium bicarbonate.
NDC 68012-104-30 Bottles
of 30 capsules
ZEGERID Powder for Oral Suspension is a white, flavored powder
packaged in unit-dose packets. Each packet contains
either
20
mg or 40 mg omeprazole and 1680 mg sodium bicarbonate.
NDC 68012-052-30 Cartons
of 30: 20-mg unit-dose packets
NDC
68012-054-30 Cartons
of 30: 40-mg unit-dose packets
Sto
rage
Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F). [See USP Controlled Room Temperature].
Keep this medication out of
the hands of children. Keep container tightly closed. Protect from
light and moisture.
17
PATIENT COUNSELING
INFORMATION
See FDA-Approved Medication Guide.
Instruct patients that ZEGERID should be taken on an empty stomach at least
one hour prior
to a meal.[See Dosage and Administration (2)]
Instruct patients in Directions for
Use
as follows:
Capsules: Swallow intact capsule with water. DO NOT USE OTHER
LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.
Powder for
Oral Suspension: Empty packet contents
into a small cup containing 1-2 tablespoons of
water. DO NOT USE OTHER LIQUIDS OR
FOODS. Stir
well and drink immediately. Refill cup with water and drink.
ZEGERID is available either
as 40 mg or
20
mg capsules with 1100 mg sodium bicarbonate. ZEGERID is also available either
as 40 mg or 20 mg single-dose packets of powder
for
oral suspension with 1680 mg sodium bicarbonate.
Patients should be instructed not to substitute ZEGERID Capsules or
Suspension for
other ZEGERID dosage forms because different dosage forms contain different amounts of
sodium bicarbonate and magnesium hydroxide. [See Dosage and Administration (2)]
Patients should be advised that since both the 20 mg and 40 mg oral suspension packets contain the same amount of sodium bicarbonate (1680
mg), two packets
of 20 mg are not equivalent to one packet of
ZEGERID 40
mg; therefore, two 20 mg packets of ZEGERID should not be substituted for
one packet of ZEGERID 40 mg. Conversely ½ of
a 40mg packet should not be substituted for
one 20mg packet. [See Dosage and Administration (2)]
Patients should be advised that since both the 20 mg and 40 mg capsules contain the same amount of sodium bicarbonate (1100 mg), two capsules
of 20 mg are not equivalent to one capsule of ZEGERID 40 mg; therefore, two 20 mg capsules of
ZEGERID should not be substituted for one capsule of ZEGERID 40 mg. [See Dosage and Administration (2)]
Patients should be advised that this drug is not approved for use in patients less than 18 years of
age. [See Pediatric Use (8.4)]
Patients on a sodium-restricted diet or patients at risk of developing congestive heart failure (CHF)
should be informed of
the sodium content of ZEGERID Capsules (304 mg per capsule)
and
ZEGERID Powder
(460 mg per packet). Patients should be informed that chronic use of
sodium bicarbonate may cause problems and increased sodium intake can cause swelling and weight gain. If this
occurs, they should contact their
healthcare provider. [See Warnings and Precautions (5.5)]
Patients should be informed that the most frequent adverse reactions
associated with ZEGERID include headache, abdominal pain, nausea, diarrhea, vomiting and flatulence. [See Adverse Reactions (6)]
Pregnant women should be advised that a harmful effect of ZEGERID on the fetus can not be ruled out and that the drug should be used with caution during pregnancy. [See Pregnancy (8.1)]
Patients should be advised to use this drug with caution if they are regularly taking calcium
supplements.[See Warnings and Precautions
(5.3)]
Advise patients to immediately report and seek care for diarrhea that does not
improve. This may be a sign of
Clostridium difficile associated diarrhea. [See Warnings and Precautions (5.6)]
Advise patients to immediately report and seek care for any cardiovascular or
neurological symptoms
including palpitations, dizziness, seizures and tetany as these may be signs of hypomagnesemia. [See Warnings and Precautions
(5.9)]
ZEGERID® Capsules
and
Powder
for Oral Suspension are manufactured for: Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Inc.,
Raleigh, NC 27615
Product protected by one or more of
the following U.S patent Nos. RE45,198; 6,780,882; 7,399,772
Please see www.salix.com for patent information.
ZEGERID® is a registered trademark of Santarus, Inc., a wholly owned
subsidiary of
Salix Pharmaceuticals, Inc., Raleigh, NC 27615
REV DEC 2014
VENART-xxxxxxx
M
EDICATION GUIDE
ZEGERID (ze ger id) (omeprazole / sodium bicarbonate)
Powder for Oral Suspension and Capsules
Read this Medication Guide before you start taking ZEGERID and each time you get a refill. There may be new information. This information does
not take the place
of talking to your doctor
about your
medical condition or treatment.
Wha
t is the most important information I should know about ZEGERID?
ZEGERID may help with your acid-related
symptoms, but you could
still have serious
stomach problems. Talk with your doctor. ZEGERID can cause serious side effects, including:
• ZEGERID contains sodium bicarbonate. Tell
your doctor if you are on a sodium restricted diet or
if you have Bartter’s
Syndrome (a rare kidney disorder).
Tell your
doctor right away if you have confusion, shaking hands, dizziness, muscle twitching, nausea, vomiting, and numbness
or tingling in the face, arms,
or legs.
• Diarrhea. ZEGERID may increase your
risk of
getting severe diarrhea.
This diarrhea may be caused by an infection (Clostridium difficile) in your
intestines.
Call your doctor
right away if
you
have watery stool, stomach pain, and fever that does not go away.
• Bone fractures. People who take multiple daily doses of
proton pump inhibitor medicines
for
a long period of
time (a year or
longer)
may
have an increased risk of fractures
of the hip, wrist or
spine. You should take ZEGERID exactly
as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your
doctor about your
risk of
bone fracture if
you take ZEGERID.
ZEGERID can have other
serious side effects.
See “What
are the possible side effects of ZEGERID?”
Wha
t is ZEGERID?
ZEGERID is
a prescription medicine called a proton pump inhibitor
(PPI).
ZEGERID reduces
the amount of acid in your
stomach. ZEGERID is used in adults:
•
for 4 weeks
to heal ulcers
in the first part of
the small bowel (duodenal ulcers). Your
doctor may prescribe another 4 weeks of ZEGERID.
•
for up to 8 weeks for healing stomach ulcers.
•
for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD).
GERD happens when acid from
the stomach backs up into the tube (esophagus)
that connects your
mouth to your stomach. This may cause a burning feeling in your chest or throat, sour
taste, or burping.
•
for up to 8 weeks to heal acid-related damage to the lining of
the esophagus (called erosive esophagitis or EE).
• to maintain healing of
the esophagus. It is not known if
ZEGERID is safe and effective if
used longer than 12 months
(1
year).
• to lower the risk of
stomach bleeding in critically ill people (40 mg Oral
Suspension only).
It
is not known if ZEGERID is
safe and effective in children less
than 18 years
of age.
Wh
o should not take ZEGERID?
Do not take ZEGERID if
you:
• are allergic to omeprazole or any of
the
other ingredients in ZEGERID. See the end of this Medication Guide for a complete list of
ingredients in ZEGERID.
• are allergic to any other proton pump inhibitor
(PPI) medicine.
Wha
t should
I tell my doctor before I
take ZEGERID? Before you take ZEGERID, tell your doctor if you:
•
have been told that you have low magnesium, calcium, or potassium
levels in your
blood
•
have liver problems
•
have heart failure
•
have Bartter’s
syndrome (a rare kidney disorder)
•
have any allergies
•
have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if ZEGERID can harm your
unborn baby.
• are breastfeeding or plan to breastfeed.
ZEGERID can pass into your
breast milk and may harm
your baby. You and your
doctor should decide if
you will take
ZEGERID or breastfeed.
You should not do both. Talk with your doctor
about the best way to feed your baby if you take ZEGERID.
Tell your doctor about all the medicines you
take, including prescription and non-prescription drugs, anti-cancer drugs, vitamins and herbal supplements. ZEGERID
may
affect how other medicines work, and other
medicines
may
affect how ZEGERID works.
Especially tell your doctor
if you take:
• Mycophenolate mofetil (Cellcept)
•
diazepam
(Valium®)
•
warfarin (Coumadin® Jantoven)
•
phenytoin (Dilantin®)
• cyclosporine (Gengraf, Neoral, Sandimmune)
•
disulfiram
(Antabuse®)
Referenc• e IDa :be3n6zo7d5ia7ze9p8ine
medicine
•
ketoconazole (Nizoral®)
• an antibiotic that contains ampicillin
•
products that contain iron
•
digoxin (Lanoxin®)
•
voriconazole (Vfend®)
• atazanavir (Reyataz®)
•
nelfinavir (Viracept®)
• tacrolimus
(Prograf®)
•
saquinavir (Fortovase®)
• clarithromycin (Biaxin®, Biaxin XL)
• clopidogrel (Plavix®)
•
St. John’s Wort (Hypericum perforatum)
•
rifampin (Rifater, Rifamate, Rimactane, Rifadin)
•
methotrexate
Ask your
doctor or
pharmacist for
a list of these medicines, if you are not sure.
Know the medicines that you take. Keep a list of them
to show your
doctor and pharmacist when you get a new medicine.
Ho
w should I take ZEGERID?
•
Take ZEGERID exactly as
prescribed by your
doctor.
•
Do not change your
dose or stop taking ZEGERID without talking to your doctor.
Take ZEGERID on an empty stomach at least one hour
before a meal.
• Empty the contents of a packet of
ZEGERID Powder for Oral Suspension into a small cup containing 1 to 2 tablespoons of
water. Do not
use other liquids or
foods. Stir well and drink immediately. Refill cup with water
and
drink.
•
Swallow ZEGERID
Capsules
whole with water. Do not
use other liquids. Do not crush or chew the capsule. Do not open the capsule and sprinkle contents into food.
•
If you miss a dose of ZEGERID, take it as soon as
you remember. If
it is almost time for
your
next dose, do not take the missed dose. Take the next dose at your
regular
time.
Do not take two doses
to make up for a missed dose.
•
Do not substitute two 20 mg packets
for
one 40 mg packet of
ZEGERID Powder for Oral Suspension because you will receive twice the amount of
sodium bicarbonate. Talk to your
doctor if you have questions.
•
Do not substitute two 20 mg capsules for one 40 mg capsule of ZEGERID because you will receive twice the amount of sodium bicarbonate. Talk to your doctor
if you have questions.
•
If you take too much ZEGERID, call your doctor
or Poison Control Center right away, or go to the nearest hospital emergency room.
•
Your doctor may prescribe antibiotic medicines with ZEGERID to help treat a stomach infection and heal stomach-area (duodenal)
ulcers
that are caused by
bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it.
•
See the “Instructions for Use” at the end of
this Medication Guide for instructions on how to mix and give ZEGERID Powder for Oral Suspension through a nasogastric tube or orogastric tube.
Wha
t are the possible side effects
of ZEGERID?
ZEGERID may cause serious side effects, including:
• See “What is the most important information
I should
know about
ZEGERID?”
• Chronic (lasting a long time) inflammation
of the stomach lining (Atrophic Gastritis).
Taking ZEGERID for a long period of time may increase the risk of
inflammation to your stomach lining. You may or may not have symptoms. Tell your
doctor if
you have stomach pain, nausea, vomiting, or weight loss.
• Vitamin B-12 deficiency. ZEGERID reduces the amount of
acid in your stomach. Stomach acid is needed to absorb vitamin B-12 properly. Talk with your
doctor about the possibility of vitamin B-12 deficiency if you have been on ZEGERID for a long time (more than 3 years).
• Low magnesium levels in your body. This problem can
be serious.
Low magnesium
can
happen in some people who take a proton pump inhibitor
medicine for at least 3 months. If
low
magnesium levels happen, it is usually after a year of
treatment. You may or may not have symptoms
of low magnesium.
Tell your
doctor right away if you develop any of
these symptoms:
•
seizures
•
dizziness
• abnormal or
fast heartbeat
• jitteriness
• jerking movements
or shaking (tremors)
•
muscle weakness
•
spasms of
the hands and feet
• cramps or
muscle aches
•
spasm of
the voice box
Your doctor may check the level of
magnesium in your body before you start taking ZEGERID, or
during treatment, if
you will be taking ZEGERID for a long period of
time.
The most common side effects
with
ZEGERID include:
•
headache
• abdominal pain
•
nausea
Refe•rencdiearrIhDea: 3675798
•
vomiting
•
gas
Other side effects:
• Serious allergic reactions. Tell your doctor if you get any of the following symptoms with ZEGERID.
•
rash
•
face swelling
• throat tightness
•
difficulty breathing
Your doctor may stop ZEGERID if
these symptoms happen.
Using ZEGERID for
a long time may cause problems such as
swelling and weight gain. Tell your
doctor if
this happens.
If you are on a low-sodium diet or at risk of
developing congestive heart failure (CHF), you and your doctor
should decide if you will take ZEGERID.
Tell your doctor if you have any side effect that bothers
you or
that
does not go away.
These are not all the possible side effects
of ZEGERID. For more information, ask your doctor
or pharmacist.
Call your doctor
for
medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
Ho
w should I store ZEGERID?
•
Store ZEGERID at room temperature between 59 °F to 86 °F (15 °C to 30 °C).
•
Keep ZEGERID Capsules in a tightly closed container.
•
Keep ZEGERID in a dry place and out of the light.
K
eep ZEGERID and all medicines out of
the
reach of children. General information about
ZEGERID
Medicines are sometimes
prescribed for purposes other
than those listed in a Medication Guide. Do not use ZEGERID for
any
condition for
which it was not prescribed by your
doctor.
Do not give ZEGERID to other people, even if they have the same symptoms as you. It may harm them.
This Medication Guide summarizes the most important information about ZEGERID. If you would like more information, talk to your
doctor. You can also ask your
doctor or
pharmacist for
information about ZEGERID that is written for
healthcare professionals.
For more information, go to www.Salix.com or 1-800-508-0024.
Wha
t are the ingredients in
ZEGERID?
Active ingredients: omeprazole and sodium bicarbonate
Inactive ingredients of ZEGERID Powder
for
Oral Suspension: xylitol, sucrose, sucralose, xanthan gum, and flavorings. Inactive ingredients of
ZEGERID Capsules: croscarmellose sodium and sodium stearyl fumarate.
Inst
ructions for Use
For instructions
on
taking ZEGERID Capsules
and ZEGERID Powder
for Oral Suspension by mouth, see “How should I take ZEGERID?” Giving ZEGERID Powder for Oral Suspension through a nasogastric tube (NG tube) or gastric tube:
•
Add 20 mL of
water
to a catheter tipped syringe and then add the contents of
a packet as prescribed by your
doctor. Use only a catheter
tipped syringe to give
ZEGERID through a NG tube or orogastric tube.
•
Shake the syringe to dissolve the powder.
•
Give the medicine through the NG or orogastric tube into the stomach right away.
• Refill the syringe with an equal amount of water.
•
Shake and flush any remaining contents from the NG tube or
orogastric tube into the stomach.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
ZEGERID® Capsules
and
Powder
for Oral Suspension
are
manufactured for
Santarus, Inc., a wholly owned subsidiary of
Salix Pharmaceuticals, Inc. Raleigh, NC 27615
This product is covered by U.S. Patent Nos: RE45,198; 6,780,882; 7,399,772.
ZEGERID® is a registered trademark of Santarus, Inc., a wholly owned subsidiary of
Salix Pharmaceuticals, Inc. Raleigh, NC 27615 2014 Santarus, Inc.
REV DEC 2014
VENART-xxxxxxx
Reference ID: 3675798
