奥美拉唑碳酸氢钠胶囊FDA说明书

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_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

ZEGERID? with Magnesium Hydroxide Chewable Tablets safely and

effectively. See full prescribing information for ZEGERID with

Magnesium Hydroxide Chewable Tablets.

ZEGERID with Magnesium Hydroxide (omeprazole/sodium

bicarbonate/magnesium hydroxide) Chewable Tablets

Initial U.S. Approval: 2004

----------------------------INDICATIONS AND USAGE---------------------------

ZEGERID with Magnesium Hydroxide Chewable Tablets is a proton pump inhibitor indicated for:

? Treatment of duodenal ulcer (1.1) ? Treatment of gastric ulcer (

1.2) ? Treatment of gastroesophageal reflux disease (GERD) (1.3) ? Maintenance of healing of erosive esophagitis (1.4)

The safety and effectiveness of ZEGERID with Magnesium Hydroxide Chewable Tablets in pediatric patients (<18 years of age) have not been established. (8.3)

----------------------DOSAGE 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) ---------------------DOSAGE FORMS AND STRENGTHS----------------------

? ZEGERID with Magnesium Hydroxide Chewable Tablets

(omeprazole/sodium bicarbonate/magnesium hydroxide) is available in 20 and 40 mg strengths (3) -------------------------------CONTRAINDICATIONS----------------------------- ? Known hypersensitivity to ZEGERID or any of the components in the

formulation ?

Patients who can not take Magnesium

-----------------------WARNINGS AND PRECAUTIONS------------------------? Concomitant Gastric Malignancy: Symptomatic response to therapy

with ZEGERID with Magnesium Hydroxide Chewable Tablets 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) Buffer Content (5.3):

______________________________________________________________________Sodium content to be taken into consideration when administering to

patients on a sodium-restricted diet

Magnesium content increases risk of hypermagnesemia and magnesium toxicity in neonates, elderly, and in patients with renal impairment or renal disease

To be used with caution in patients with Bartter’s syndrome,

hypokalemia, respiratory alkalosis, and problems with acid-base balance because of its sodium bicarbonate content; long-term administration of bicarbonate with calcium or milk can cause milk-alkali syndrome ------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence ≥ 2%) are:

Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence (6) To report SUSPECTED ADVERSE REACTIONS, contact Santarus Inc.

at 1-888-778-0887, option 2 or https://www.360docs.net/doc/718385008.html,/contact/, or FDA

at 1-800-FDA-1088 or https://www.360docs.net/doc/718385008.html,/medwatch.

------------------------------DRUG INTERACTIONS-------------------------------

? Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin,

phenytoin, cyclosporine, disulfiram, benzodiazepines): ZEGERID with

Magnesium Hydroxide Chewable Tablets can prolong their elimination.

Monitor to determine the need for possible dose adjustments when taken

with ZEGERID with Magnesium Hydroxide Chewable Tablets (7)

? Patients treated with proton pump inhibitors and warfarin concomitantly

may need to be monitored for increases in INR and prothrombin time

(7) ? Drugs for which gastric pH can affect bioavailability (e.g.,

ketoconazole, ampicillin esters, iron salts): ZEGERID with Magnesium

Hydroxide Chewable Tablets may interfere with absorption due to

inhibition of gastric acid secretion (7)

? Voriconazole: May increase plasma levels of omeprazole (7)

? ZEGERIDwith Magnesium Hydroxide may reduce plasma levels of

atazanavir and nelfinavir (7)

? ZEGERIDwith Magnesium Hydroxide may increase serum levels of

tacrolimus, voriconazole, saquinavir, and clarithromycin (7) -----------------------USE IN SPECIFIC POPULATIONS-----------------------

? Pregnancy: Based upon animal data, may cause fetal harm (8.1) ? The safety and effectiveness of ZEGERID with Magnesium Hydroxide

in pediatric patients less than18 years of age have not been established.

(8.4) ? Hepatic Impairment: Consider dose reduction, particularly for

maintenance of healing of erosive esophagitis (12.3)

See 17 for PATIENT COUNSELING INFORMATION Revised: January 2010 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

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 Buffer Content

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

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 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? with Magnesium Hydroxide 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 Gastric Ulcer

ZEGERID with Magnesium Hydroxide 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 with Magnesium Hydroxide is indicated for the treatment of heartburn and other symptoms associated with GERD. [See Clinical Studies (14.3)]

Erosive Esophagitis

ZEGERID with Magnesium Hydroxide is indicated for the short-term treatment (4-8 weeks) of erosive esophagitis which has been diagnosed by endoscopy.

The efficacy of ZEGERID with Magnesium Hydroxide 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 omeprazole may be considered. [See Clinical Studies (14.3)]

1.4 Maintenance of Healing of Erosive Esophagitis

ZEGERID with Magnesium Hydroxide is indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4)]

2 DOSAGE AND ADMINISTRATION

ZEGERID with Magnesium Hydroxide (omeprazole/sodium

bicarbonate/magnesium hydroxide) is available as chewable tablets in 20 mg and 40 mg strengths 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 tablets contain the same amount of sodium bicarbonate (600 mg) and magnesium hydroxide (700 mg), two 20 mg chewable tablets are not equivalent to one 40 mg tablet; therefore, two 20 mg tablets should not be substituted for one 40 mg tablet. Conversely a half of one 40mg tablet should not be substituted for one 20 mg tablet.

Because ZEGERID with Magnesium Hydroxide chewable tablets contain Magnesium Hydroxide, the chewable tablets should not be substituted for other ZEGERID dosage forms (e.g., ZEGERID Powder for Oral Suspendion or ZEGERID Capsules).

ZEGERID with Magnesium Hydroxide should be taken on an empty stomach at least one hour before a meal.

Table 1: Recommended Doses of Zegerid with Magnesium Hydroxide 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

Once daily for

up to 4

weeks+

Once daily for

4-8 weeks+

Maintenance of

Healing of Erosive

Esophagitis

20 mg Once daily**

* Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. [See Clinical Studies (14.1)]

** For additional information, [See Clinical Studies (14)].

+ For additional information, [See Indications and Usage (1)].

Special Populations

Hepatic Insufficiency

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)]

Administration of Chewable Tablets

ZEGERID with Magnesium Hydroxide chewable tablets should be chewed and swallowed with water. DO NOT SWALLOW WHOLE. DO NOT USE OTHER LIQUIDS. DO NOT SUBSTITUTE FOR OTHER ZEGERID DOSAGE FORMS.

3 DOSAGE FORMS AND STRENGTHS

ZEGERID with Magnesium Hydroxide 20-mg Chewable Tablets: Each pink, 18 mm in diameter, round tablet, inscribed with the number “2031” on one side and the Santarus logo on the other side, contains 20 mg omeprazole and 600 mg sodium bicarbonate plus 700 mg magnesium hydroxide. ZEGERID with Magnesium Hydroxide 40-mg Chewable Tablets: Each pink, 18 mm in diameter, round tablet, inscribed with the number “4031” on one side and the Santarus logo on the other side, contains 40 mg omeprazole and 600 mg sodium bicarbonate plus 700 mg magnesium hydroxide.

4 CONTRAINDICATIONS

ZEGERIDwith Magnesium Hydroxide is contraindicated in patients with known hypersensitivity to any components of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria.

ZEGERID with Magnesium Hydroxide is contraindicated in patients who cannot take magnesium. [See Warnings and Precautions (5.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Concomitant Gastric Malignancy

Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.

5.2 Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.

5.3 Buffer Content

Each 20 mg and 40 mg ZEGERIDwith Magnesium Hydroxide chewable tablet contains 600 mg (7 mEq) of sodium bicarbonate (equivalent to 164 mg of Na+) and 700 mg (24 mEq) of magnesium hydroxide (equivalent to 292 mg of Mg++).

Sodium Bicarbonate

The sodium content of this product 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. Magnesium Hydroxide

Because ZEGERID with Magnesium Hydroxide contains magnesium hydroxide, it should be used with caution in,the elderly and patients with renal impairment or renal disease due to increased risk of developing hypermagnesemia and magnesium toxicity. Magnesium hydroxide should not be used in patients with renal failure unless serum magnesium levels are being closely monitored.

Hypermagnesemia has been reported in infants whose mothers were using magnesium-containing antacid products chronically in high doses.

6 ADVERSE 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.

Table 2: Adverse Reactions Occurring in 1% or More of Patients on

Omeprazole Therapy

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 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% Causal Relationship

not Assessed

Omeprazole Placebo

(n = 2631) (n = 120) 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 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

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

Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy, hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests (ALT, AST, GGT, alkaline phosphatase, and bilirubin)

Metabolic/Nutritional

Hyponatremia, hypoglycemia, and weight gain.

Musculoskeletal

Muscle cramps, myalgia, muscle weakness, joint pain, 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.

The use of magnesium hydroxide is associated with diarrhea, abdominal cramping, chalky taste, diuresis, dehydration, nausea, and vomiting.

7 DRUG INTERACTIONS

Drugs for which gastric pH can affect bioavailability

Because of itsinhibition 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 efficacy trials antacids were used concomitantly with the administration of omeprazole.

Drugs metabolized by cytrochrom 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 ZEGERIDwith Magnesium Hydroxide.

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.

Antiretroviral 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 reduct 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. 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.

Antimicrobials

Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and 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. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Table 3: Clarithromycin Tissue Concentrations

2 hours after Dose1

Tissue Clarithromycin

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)

Mean ± (μg/g)

Tacrolimus

Concomitant administration of omeprazole and tacrolimus may increase the

serum levels of tacrolimus.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies on the use of omeprazole in pregnant women. The vast majority of reported experience with omeprazole

during human pregnancy is first trimester exposure and the duration of use is

rarely specified, e.g., intermittent versus chronic. An expert review of

published data on experiences with omeprazole use during pregnancy by

TERIS – the Teratogen Information System – concluded that therapeutic

doses during pregnancy are unlikely to pose a substantial teratogenic risk (the

quantity and quality of data were assessed as fair).1

Three epidemiological studies compared the frequency of congenital

abnormalities among infants born to women who used omeprazole during

pregnancy to the frequency of abnormalities among infants of women exposed

to H2-receptor antagonists or other controls. A population-based prospective

cohort epidemiological study from the Swedish Medical Birth Registry,

covering approximately 99% of pregnancies, 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.2 In utero exposure to omeprazole was not

associated with increased risk of any malformation (odds ratio 0.82, 95% CI

0.50-1.34), low birth weight or low Apgar score. 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 the

normal population. The author concluded that both effects may be random.

A retrospective cohort study reported on 689 pregnant women exposed to

either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole).3 The overall malformation rate was 4.4% (95% CI 3.6-5.3) and

the malformation rate for first trimester exposure to omeprazole was 3.6%

(95% CI 1.5-8.1). The relative risk of malformations associated with first

trimester exposure to omeprazole compared with nonexposed women was 0.9

(95% CI 0.3-2.2). The study could effectively rule out a relative risk greater

than 2.5 for all malformations. Rates of preterm delivery or growth retardation

did not differ between the groups.

A controlled prospective observational study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures).4 The reported

rates of major congenital malformations was 4% for the omeprazole group,

2% for controls exposed to nonteratogens, and 2.8% in disease-paired controls (background incidence of major malformations 1-5%). Rates of spontaneous

and elective abortions, preterm deliveries, gestational age at delivery, and

mean birth weight did not differ between the groups. The sample size in this

study has 80% power to detect a 5-fold increase in the rate of major

malformation.

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.

Hypermagnesemia has been reported in infants whose mothers were using

magnesium-containing antacid products chronically in high doses.

Reproduction studies conducted with omeprazole in rats at oral doses up to 28

times the human dose of 40 mg/day, (based on body surface area) and in

rabbits at doses up to 28 times the human dose (based on body surface area)

did not show any evidence of teratogenicity. In pregnant rabbits, omeprazole

at doses about 2.8 to 28 times the human dose of 40 mg/day, (based on body

surface area) produced dose-related increases in embryo-lethality, fetal

resorptions, and pregnancy loss. In rats treated with omeprazole at doses about

2.8 to 28 times the human dose (based on body surface area), dose-related

embryo/fetal toxicity and postnatal developmental toxicity occurred in

offspring. [See Animal Toxicology and/or Pharmacology (13.2)].

There are no adequate and well-controlled studies in pregnant women. Because animal studies and studies in humans cannot rule out the possibility of harm, ZEGERID with Magnesium Hydroxide Chewable Tablets should be used during pregnancy only if the potential benefit to pregnant women justifies the potential risk to the fetus.

8.3 Nursing 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 with Magnesium Hydroxide Chewable Tablets have not been established in pediatric patients.less than 18 years of age.

8.5 Geriatric 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 with Magnesium Hydroxide. However, no dosage adjustment is necessary in the elderly. [See Clinical Pharmacology (12.3)]

8.6 Hepatic Impairment

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)]

8.7 Renal Impairment

No dose reduction is necessary. However, ZEGERID with Magnesium Hydroxide chewable tablets contains 700mg (24mEq) magnesium hydroxide (equivalent to 292 mg of Mg2+); therefore, magnesium levels should be closely monitored when using this product in patients with renal impairment. [See Clinical Pharmacology (12.3)]

8.8 Asian Population

Recommend dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)]

10 OVERDOSAGE

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.

Similarly, a magnesium overdose may lead to hypermagnesemia.

Hypermagnesemia results in a depressant effect on the central nervous system,

causing anorexia and nausea, and neuromuscular system. Magnesium toxicity

causes hypotension, muscle weakness, and electrographic changes.

11 DESCRIPTION

ZEGERID? with Magnesium Hydroxide (omeprazole/sodium

bicarbonate/magnesium hydroxide) is a combination of omeprazole, a proton-

pump inhibitor, and sodium bicarbonate plus magnesium hydroxide, both of

which are antacids. 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 with Magnesium Hydroxide chewable tablets are available in two

strengths containing 40 mg and 20 mg of omeprazole, and is formulated as an

immediate-release chewable tablet. Each chewable tablet contains either

40 mg or 20 mg of omeprazole and 600 mg of sodium bicarbonate plus

700 mg of magnesium hydroxide with the following inactive ingredients:

hydroxypropyl cellulose, croscarmellose sodium, xylitol, sucralose, flavoring,

magnesium stearate, and FD&C Red #40 Aluminum Lake.

12 CLINICAL 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 with Magnesium Hydroxide is an immediate-release chewable

tablet formulation that contains an antacid component (sodium bicarbonate

plus magnesium hydroxide) which raises the gastric pH and thus protects

omeprazole from acid degradation.

12.2 Pharmacodynamics

Antisecretory Activity: Results from PK/PD studies of the antisecretory effect

of repeated once-daily dosing of 40 mg and 20 mg of ZEGERID with

Magnesium Hydroxide chewable tablets in healthy subjects are shown in

Table 4 below.

Table 4: Effect of ZEGERID? with Magnesium Hydroxide on

Intragastric Ph, Day 7

Omeprazole/Sodium

Bicarbonate/

Magnesium Hydroxide

Parameter

40 mg/600 mg/

700 mg

(n = 35)

20 mg/600 mg/

700 mg

(n = 29)

% Decrease from Baseline 73% 72%

for Integrated Gastric

Acidity (mmol*h r/L)

Coefficient of variation 19% 28%

% Time Gastric pH > 4 62% 57%

(Hours) (14.9 h) (13.8 h)

Coefficient of variation 30% 32%

Median pH 5.1 4.8

Coefficient of variation 24% 29%

Note: Values are medians. All parameters were measured over a 24-hour

period.

The antisecretory effect of omeprazole 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 g a strin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic dos e s of omeprazole in parallel with inhibition of acid secretion. No further increas e in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 m g 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, cholecysto k inin, 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 health y 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 intragastr i c concentrations of viable bacteria. The pattern of the bacterial species w a s unchanged from that commonl y found in saliva. All changes resolved within three days of stopping treatment .

The course o f 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 mon t hs followed by 20 mg b.i.d. for 12 months or ranitidine 300 mg b.i.d. for 2 4 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

When ZEGERID with Magnesium Hydroxide chewable tablets are administered on an empty stomach at leas t 1 hour prior to a meal, the absorption of omeprazole is rapid, with a mean peak plasma level (%CV) of omeprazole being 1763 ng/mL (25%) and time to peak of approximately 30 minutes (range 10-90 min) after a single-dose or repeated-dose administration. Following single or repeated once daily dosing, peak plasma concentrations of omeprazole from ZEGERID with Magnesium Hydroxide are approximately proportional to those from 20 to 40 mg doses of omeprazole, but a greate r than linear mean AUC (three-fold increase) is observed when do u bling the dose to 40 mg. The bioavailability of omeprazole from ZEGERID with Magnesium Hydroxide increases upon repeated administration.

When ZEGERID with Magnesium Hydroxide che w able tablets are administered 1 hour after a meal, the AUC is reduced by approximately 22% 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 plas m a – 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 app r oximately 1 hour (range 0.4 to 3.1 hours) and the total body clear a nce is 500-600 mL/min.

Special 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 o f omeprazole was 250 m L/min (about half that of young subjects) and its plasma half-life averaged one hour, similar to that of young healthy subjects.

Pediatric

The pharm a cokinetics of ZEGERID with Magnesium Hydroxide have not been studied in patients < 18 years of age.

Gender

There are no known di f ferences 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 subjec t s. Dose reduction, particularly where maintenance of healing of ero s ive 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 the r e was a slight increase in bioavailability. Because urinary excretion is a p r imary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the d e creased creatinine clearance. No dose reduc t ion is necessary in patien t s with renal impairment.

ZEGERID with Magnesium Hydroxide chewable tablets contain magnesium hydroxide (292 m g of M g++); therefore, magnesium levels should be closely monitored when using this product in patients with renal failure.

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 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis,

Mutagenesis, Impairment of Fertility

In two 24-month c a rcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (approximately 0.35 to 28.5 times the human dose of 40 mg/day, based on body surface area) produced gastric EC L 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 hig h er blood levels of omeprazole. Gastric carcinoids seldo m occur in the untreated rat. In addition, ECL cell hyperplasia was p r esent in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 m g omeprazole/kg/day (approximately 2.8 times the human dose of 40 mg/day, based on body surface area) 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 omeprazol e at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.3 times the human dose of 40 mg/day, based on body surface area). 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 28.5 times the human dose of

40 mg/day, based on body surface area). A 78-week mouse carcinogenicity 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 vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames Test, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) 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 at doses up to 138 mg/kg/day (about 28 tim e s the human dose of 40 mg/day, based on body surface area) and in pregnant rabbits at doses up to 69 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) did not disclose an y evidence for a teratogenic potential of omeprazole. In rabbits, o m eprazole in a dose ra n ge of 6.9 to 69 mg/kg/day (about 2.8 to 28 times the human dose of 40 m g/ d ay, based on body surface area) produced d o se-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 mg/kg/day (about 2.8 to 28 times the human dose of 40 mg/day, based on body surface area).

14 CLINICAL 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 5)

Table 5: Treatment of Acti v e Duodenal Ulcer % of Patients Healed

Omep r azole Placebo

20 mg a.m. a.m.

(n = 99) (n = 48)

Week 2 41* 13

Week 4 75* 27

* (p ≤ 0.01)

Daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omepra z ole 20 mg th a n in patients treated with place b o. At the end of the study, significantly mor e patients who had received omeprazole had complete re l ief of daytime pain (p ≤ 0.05) and n i ghttime pain (p ≤ 0.01).

In a mul t icenter, d o uble-blind study of 293 patients with endoscopically documented duodenal ulcer, the perce n tage 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 6)

Table 6: Treatment of Active Duodenal Ulcer % of Patients Healed

20 mg a.m.

Omeprazole

(n = 145)

150 mg b.i.d.

Ranitidine

(n = 148)

Week 2 42 34

Week 4 82* 63

* (p < 0.01)

Healing occurred significantly faster in patients treated with omeprazole than

in those treated with ranitid i ne 150 mg b.i .d. (p < 0.0 1).

In a foreign multinational ra n domized, do u ble-blind study of 105 p a tients with endoscopically documented d u odenal ulc e r, 40 mg an d 20 mg of omeprazole were com p ared to 150 mg twice a day of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omep r azole were statistically superior (per protocol) to ranitidine, but 40 m g was not superior to 20 mg o f omeprazole, and at 8 weeks there was no significant difference between any of the active drugs. (See Table 7)

Table 7: Treatment of Active Duodenal Ulcer % o f Patients Healed

Omeprazole 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

Week 8 100 100 94

*(p ≤ 0.01)

14.2 Gastric

Ulc

e r

In a U. S. multicenter, double-blind, study of omep r azole 40 mg once a d a y, 20 mg once a day, and placebo in 520 patients with endoscop i cally diag n osed gastric ulce r, the followin g resu l ts were obta i ned. ( S ee Table 8)

Table 8: Treatm e nt of Gastric Ulcer % of Patients Healed

(All Patients Tr e ated )

Omeprazole

40 mg q.

(n = 214)

Omeprazole

20 mg q.d.

(n = 202)

Placebo

(n = 104) 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 9)

Table 9: Treatment of Gastric Ulcer

% of Patients Healed (All Patients Treated)

Omeprazole Omeprazole Ranitidine

40 mg q.d. 20 mg q.d 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 **(p < 0.01) Omeprazole 40 mg versus ranitidine ++(p < 0.01) Omeprazole 40 mg versus 20 mg 14.3 Gastroesophageal 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 s y mptoms in

GERD patients without erosive esophagitis. Results are shown in Table 10.

Table 10: % Succes s ful S y mptomatic Outco

m e a Omeprazole

Omeprazole

Placebo

m. 20 mg a. m. 10 mg a. a.m. All patients 46*,? (n = 205) 31? (n = 199)13 05) (n = 1 Patients with

confirmed GERD

56*,? (n = 115) 36? (n = 109) 14 (n = 59) 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 in patients with symptoms of GERD

and endoscopically diagnosed erosive esophagitis of grade 2 or above, the

percentage h e aling rates (per protocol) were as shown in Table 11 .Table 11: % Patient s Healed Omeprazole

Omeprazole

Placebo

40 mg

20 mg

(n = 43) (n = 87)

(n = 83)

Week 4 45* 39* 7 Week 8

75*

74*

* (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, grad e 2 or above, omeprazole in a dose of 20 mg was significan t ly more eff e ctive than the active controls. Com p lete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patie n ts tr e ated with omeprazole than in those taking placebo or histamine H2-receptor antagonists. In this and fi v e other c o ntrolled GERD stu d ies, sign i ficantly mor e patients taking 20 mg omeprazole (84%) reported com p lete r e lief of GERD symptoms than patients receiving placebo (12%). 14.4 Long Term Maintenance Treatm

e nt o

f 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 maintenance of healin

g of erosive esophagitis are shown in Table 12.

Table 12: Life Table Analysis Omeprazole 20 mg q.d. (n = 138) 137) Omeprazole 20 mg 3 days per week (n = (n = 131)Placebo

Percent in

endoscopic remission 70* 34 11 at 6 months

* (p < 0.01) Omeprazole 20 mg q.d. 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 13 provides th e results of this study for maintenance of healing of erosive esop h agitis. Table 13: Life Table Analysis 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 months

77*

58?

* (p = 0.01) Omeprazole 20 mg q.d. versus Omeprazole 10 mg q.d. or Ranitidine. ? (p = 0.03) Omeprazole 10 mg q.d. versus Ranitidine. In patients who initially had grades 3 or 4 erosive esophagitis, for

maintenance after healing , 20 mg daily of omeprazole was eff e ctive, while 10 mg did not demonstrat e effectivenes s . 15 REFERENCES

1. Friedman J M and Polifka JE. Omeprazole. In: Teratogenic Effects of

Drugs. A Resource for Clinicians (TERIS). 2nd ed. B a ltimore, MD : Th

e Johns Hopkins University Press 2000; p. 516. 2. Kallen BAJ. Use o

f omeprazole durin

g pregnancy – no hazard

demonstrate

d in 955 infants exposed during pregnancy. Eur Obstet Gynecol Reprod Biol 2001; 96(1):63-8. 3. Ruigómez A, Rodriquez LUG, Cattaruzzi C, et al. Us

e o

f cimetidine,

omeprazole, and ranitidine in pregnant women and pregnancy outcomes.

Am J Epidemiol 1999; 150: 476-81.

4. Lalkin A, Loebstein, Addis A, et al. The safety of o

m eprazole during pregnancy: a multi c enter prospective controlled study .Am J Obstet Gynecol 1998: 179:727 -30. 16

HOW SUPPLIED/ST O RAGE AN

D HANDLING ZEGERID with Magnesium Hydroxi

d e 20-mg Chewable Tablets: Each pink, 18 mm in diameter, round tablet, inscribed with the number:”2031” on

one side and the Santarus logo on the other side, contains 20 mg omepr zole a

and 600 mg sodium bicarbonate plus 700 mg magnesium hydroxide. NDC 68012-152-30

Bottles of 30 chewable tablets ZEGERID with Magnesium Hydroxide 40-mg Chewable Tablets:

Each pink, 18 mm in diameter, round tablet, inscribed with the number “4031” on

one side and the Santarus logo on the othe r side, contains 40 mg omeprazole and 600 mg sodium bicarbonate pl

u s 700 mg magnesium hydroxide. NDC 68012-154-30 Bottles of 30 chewable tablets Sto r age

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP

Controlled Room Temperature]. Do not store this product at temperatures above 30°C (86°F).

Keep this medication out of the hands of children. Keep container tightly

closed. Protect from light and moisture. 17

PATIENT COUNSELING INFORMATION

Instruct patients to take ZEGERID with Magnesium Hydroxide chewable tablets on an empty stomach at least one hour prior to a meal. [See Dosage

and Administration (2)]

PATIENTS SHOULD BE INSTRUCTED TO CHEW THE TABLET

AND SWALLOW WITH WATER . DO NOT USE OTHER LIQUIDS. PATIENTS SHOULD BE INSTRUCTED TO NOT SUBSTITUTE ZEGERID WITH MAGNESIUM HYDROXIDE C

H EWABLE TABLETS FOR OTHER ZEGERID DOSAGE FO

R MS because different dosage forms contain different amounts of sodium bicarbonate

and magnesium hydroxide.

[See Dosage and Administration (2)] ZEGERID with Magnesium Hydroxide chewable tablets are available in

40 mg and 20 mg dosage strengths of omeprazole with 600 mg sodium

bicarbonate plus 700 mg magnesium hydroxide per ta

b let. Patients should be instructed to not substitute two 20 mg chewable tablets for

one 40 m

g chewable tablet because the 20 mg and 40 mg chewable tablets contain the same amount of sodium bicarbonate (600 mg) and magnesium

hydroxide (700 mg). Substituting two 20 mg chewable tablets for one 40 m

g chewable tablet woul

d result in th

e patient receiving twice as much sodium bicarbonate and magnesium hydroxide. Conversely patients should not

substitute ? of a 40mg chewable tablet for a 20mg chewable tablet.[See

Dosage and Administration (2)]

Patients should be advised that this dru g is not approv e d for use in patients less than 18 years of age. [See Pediatri c Use (8.4)]

Patients on a sodium-restricted diet or p a tients at risk of developing

congestive heart failure (CHF) should be informed of the sodium content of

ZEGERID with Magnesium Hydroxide ch e wable tablets. Patients should be

informed that chronic use of sodium bicar b onate m

a y 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 (5.3)]

Patients should be informed that the most frequent adverse reactions associated with ZEGERID with Magnesium Hydroxide chewable tablets include headache, abdominal pain, nausea, diarrhea, vomiting and flatulence . [See Adverse Reactions (6)]

Pregnant women should be advised that a harmful effect of ZEGERID with Magnesium Hydroxide chewable tablets on the fetus can not be ruled out an d 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 reg u larly taking calcium supplements. [See Warnings and Precautions (5.3)]

ZEGERID? with Magnesium Hydroxide Chewable Tablets are manufact u red for Santarus, Inc., San Diego, CA 92130 by: Patheon Pharmaceuticals, Inc. Cincinnati, OH 45237

For more information call 1-888-778-0887

ZEGERID? is a registered trademark of Santarus, Inc.

This product is covered by one or more of the following: U.S. Patent Nos. 5,840,737; 6,489,346; 6,699,885; 6,780,882; 6,645,988, and 7,399,772 a n d additional patents pending.

? 2009 Santarus, Inc.

___________________________________________________________________________________________________________________________

_______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZEGERID (omeprazole/sodium bicarbonate) Powder for Oral Suspension and Capsules safely and effectively. See full prescribing information for ZEGERID Powder for Oral Suspension and Capsules.

ZEGERID (omeprazole/sodium bicarbonate) Powder for Oral Suspension and Capsules Initial U.S. Approval: 2004

----------------------------INDICATIONS AND USAGE--------------------------- ZEGERID Powder for Oral Suspension and Capsules 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 Powder for Oral Suspension and Capsules in pediatric patients (<18 years of age) have not been established. (8.3) ----------------------DOSAGE 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 ---------------------DOSAGE FORMS AND STRENGTHS---------------------- ? ZEGERID (omeprazole/sodium bicarbonate) is available as a capsule and as a powder for oral suspension in 20 mg and 40 mg strengths (3) -------------------------------CONTRAINDICATIONS----------------------------- ? Known hypersensitivity to any components of the formulation (4) -----------------------WARNINGS AND PRECAUTIONS------------------------? Concomitant Gastric Malignancy: Symptomatic response to therapy with ZEGERID Powder for Oral Suspension and Capsules 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) ? Buffer Content (5.3):

Sodium content to be taken into consideration when administering to patients on a sodium-restricted diet

To be used with caution in patients with Bartter’s syndrome,

------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (incidence ≥ 2%) are:

Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence (6) To report SUSPECTED ADVERSE REACTIONS, contact Santarus Inc. at 1-888-778-0887, option 2 or https://www.360docs.net/doc/718385008.html,/contact/, or FDA at 1-800-FDA-1088 or https://www.360docs.net/doc/718385008.html,/medwatch.------------------------------DRUG INTERACTIONS------------------------------- ? 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) ? Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time (7) ? Drugs for which gastric pH can affect bioavailability (e.g., ketoconazole, ampicillin esters, iron salts): ZEGERID may interfere with absorption due to inhibition of gastric acid secretion (7) ? Voriconazole: May increase plasma levels of omeprazole (7) ? ZEGERID may reduce plasma levels of atazanavir and nelfinavir (7) ? ZEGERID may increase serum levels of tacrolimus, voriconazole, saquinavir, and clarithromycin (7) -----------------------USE IN SPECIFIC POPULATIONS----------------------- ? Pregnancy: Based upon animal data, may cause fetal harm (8.1) ? The safety and effectiveness of ZEGERID in pediatric patients less than18 years of age have not been established. (8.4) ? Hepatic Impairment: Consider dose reduction, particularly for maintenance of healing of erosive esophagitis (12.3) See 17 for PATIENT COUNSELING INFORMATION

Revised: January 2010 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 Buffer Content

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.3 Nursing Mothers 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 8.4 Pediatric Use

* Sections or subsections omitted from the full prescribing information are 8.5 Geriatric Use

not listed.

FULL PRESCRIBING INFORMATION:

1 INDICATIONS AND USAGE

1.1 D uodenal 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 G astric 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. [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 Maintenance 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 Reduction 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 DOSAGE 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)

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**

Reduction of Risk

of Upper

Gastrointestinal

Bleeding in Critically

Ill Patients

(40 mg oral

suspension only)

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)]

** For additional information, [See Clinical Studies (14)]

+ For additional information, [See Indications and Usage (1)]section Special Populations

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 DOSAGE 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 CONTRAINDICATIONS

ZEGERID is contraindicated in patients with known hypersensitivity to any components of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria.

5 WARNINGS AND PRECAUTIONS

5.1 Concomitant Gastric Malignancy

Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.

5.2 Atrophic gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.

5.3 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.

6 ADVERSE 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.

definitely related to the drug.

Table 2: Adverse Reactions Occurring In 1% or More of Patients on

Omeprazole Therapy

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

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

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% Causal Relationship not Assessed

Omeprazole Placebo

(n = 2631) (n = 120) 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

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.

Table 4: Number (%) of Critically Ill Patient with Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood Frequently Occurring (≥ 3%) Adverse Events by Body pressure, and peripheral edema.

System and Preferred Term

ZEGERID? Cimetidine

(N=178) (N=181) MedDRA

Body System All AEs All AEs Preferred Term 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) 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) Ventricular Tachycardia 8 (4.5) 6 (3.3) Constipation 8 (4.5) 8 (4.4) Diarrhea NOS 7 (3.9) 15 (8.3) Gastric Hypomotility 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) 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) Hypertension NOS 14 (7.9) 6 (3.3) Hypotension NOS 17 (9.6) 12 (6.6) * 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 Gastrointestinal

Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis. 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.

Metabolic/Nutritional

Hyponatremia, hypoglycemia, and weight gain.

Musculoskeletal

Muscle cramps, myalgia, muscle weakness, joint pain, and leg pain. Nervous System/Psychiatric

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

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 DRUG INTERACTIONS

Drugs for which gastric pH can affect bioavailability

Because of its inhibition 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 efficacy trials, antacids were used concomitantly with the administration of omeprazole.

Drugs metabolized by cytrochrom P450 (CYP)

benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with ZEGERID.

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.

Antiretroviral Agents

administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. 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. Antimicrobials

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. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Table 3: Clarithromycin Tissue Concentrations

2 hours after Dose 1

Tissue Clarithromycin Clarithromycin + Omeprazole

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 ± (μg/g)

Tacrolimus

Concomitant administration of omeprazole and tacrolimus may increase the

serum levels of tacrolimus. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies on the use of omeprazole in pregnant women. The vast majority of reported experience with omeprazole during human pregnancy is first trimester exposure and the duration of use is

rarely specified, eg, intermittent versus chronic. An expert review of published data on experiences with omeprazole use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic

doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as fair).1

Three epidemiological studies compared the frequency of congenital

abnormalities among infants born to women who used omeprazole during pregnancy to the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based prospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, 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.2 In utero exposure to omeprazole

was not associated with increased risk of any malformation (odds ratio 0.82,

95% CI 0.50-1.34), low birth weight or low Apgar score. 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 the normal population. The author concluded that both effects may

be random.

A retrospective cohort study reported on 689 pregnant women exposed to

either H2-blockers or omeprazole in the first trimester (134 exposed to

omeprazole).3 The overall malformation rate was 4.4% (95% CI 3.6-5.3) and the malformation rate for first trimester exposure to omeprazole was 3.6% (95% CI 1.5-8.1). The relative risk of malformations associated with first trimester exposure to omeprazole compared with nonexposed women was 0.9 (95% CI 0.3-2.2). The study could effectively rule out a relative risk greater than 2.5 for all malformations. Rates of preterm delivery or growth

retardation did not differ between the groups.

A controlled prospective observational study followed 113 women exposed to

omeprazole during pregnancy (89% first trimester exposures).4 The reported

rates of major congenital malformations was 4% for the omeprazole group,

2% for controls exposed to nonteratogens, and 2.8% in disease-paired

controls (background incidence of major malformations 1-5%). Rates of

spontaneous and elective abortions, preterm deliveries, gestational age at

delivery, and mean birth weight did not differ between the groups. The

sample size in this study has 80% power to detect a 5-fold increase in the rate

of major malformation.

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.

Reproduction studies conducted with omeprazole in rats at oral doses up to 28

times the human dose of 40 mg/day (based on body surface area) and in

rabbits at doses up to 28 times the human dose (based on body surface area)

did not show any evidence of teratogenicity. In pregnant rabbits, omeprazole

at doses about 2.8 to 28 times the human dose of 40 mg/day, (based on body

surface area) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with omeprazole at doses about 2.8 to 28 times the human dose (based on body surface area), dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred in

offspring. [See Animal Toxicology and/or Pharmacology (13.2)]. There are no adequate and well-controlled studies in pregnant women.

Because animal studies and studies in humans cannot rule out the possibility

of harm, ZEGERID should be used during pregnancy only if the potential benefit to pregnant women justifies the potential risk to the fetus.

8.3

Nursing 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.

8.5 Geriatric Use

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 Hepatic Impairment

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)] 8.7 Renal Impairment No dose reduction is necessary. [See Clinical Pharmacology (12.3)] 8.8 Asian Population

Recommend dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)] 10 OVERDOSAGE 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 DESCRIPTION

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

C 17H 19N 3O 3

S, 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 CLINICAL 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

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 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.

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 vivo bioavailability 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.

Special 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 NONCLINICAL 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 0.35 to 28.5 times the human dose of 40 mg/day, based on body surface area) 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 2.8 times the human dose of

40 mg/day, based on body surface area) 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 3.3 times the human dose of 40 mg/day, based on body surface area). 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 28.5 times the human dose of

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse

micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames Test, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) 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 at omeprazole doses up to 138 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) and in pregnant rabbits at doses up to 69 mg/kg/day (about 28 times the human dose of 40 mg/day, based on body surface area) 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 2.8 to 28 times the human dose of 40 mg/day, based on body surface area) 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 2.8 to 28 times the human dose of 40 mg/day, based on body surface area).

14 CLINICAL STUDIES

14.1 Duodenal Ulcer Disease

Table 6: Treatment of Active Duodenal Ulcer

% of Patients Healed

20 mg a.m. a.m.

(n = 99) (n = 48)

Week 4 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

20 mg a.m. 150 mg b.i.d.

(n = 145) (n = 148)

Week 4 82* 63

* (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)

Table 8: Treatment of Active Duodenal Ulcer % of Patients Healed

40 mg 20 mg 150 mg b.i.d.

(n = 36) (n = 34) (n = 35)

Week 4 100* 97* 82

Week 8 100 100 94

*(p ≤ 0.01)

14.2 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. (See Table 9)

Table 9: Treatment of Gastric Ulcer % of Patients Healed

(All Patients Treated)

Omeprazole Omeprazole Placebo

40 mg q.d.

(n = 214)

20 mg q.d.

(n = 202)

(n =

104) Week 8 82.7**,+ 74.8** 48.1 + (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) Table 10: Treatment of Gastric Ulcer % of Patients Healed

(All Patients Treated)

Omeprazole

40 mg q.d.

(n = 187)

Omeprazole

20 mg q.d.

(n = 200)

150 mg

b.i.d.

(n = 199) Week

78.1**,++ 63.5 56.3

Week

91.4**,++ 81.5 78.4

**(p < 0.01) Omeprazole 40 mg versus ranitidine

++(p < 0.01) Omeprazole 40 mg versus 20 mg

14.3 Gastroesophageal 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.

Table 11: % Successful Symptomatic Outcome a

20 mg a.m. 10 mg a.m. a.m.

,? ?

All patients

(n = 205) (n = 199) (n = 105)

Patients with confirmed 56*,? 36? 14

GERD (n = 115) (n = 109) (n = 59)

* (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.

Table 12: % Patients Healed

40 mg 20 mg Placebo

(n = 87) (n = 83) (n = 43)

Week 8 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 maintenance of healing of erosive esophagitis are shown in Table 13.

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 remission at 6 months

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.

Table 14: Life Table Analysis

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

* (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 Reduction 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 REFERENCES

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 Biol 2001; 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 Epidemiol 1999; 150: 476-81

4. Lalkin A, Loebstein, Addis A, et al. T he safety of omeprazole during

pregnancy: a multicenter prospective controlled study. Am J Obstet

Gynecol 1998: 179:727-30.

16 HOW 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

Storage

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

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 ? 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 tablet) 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 (5.3)]

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)] ZEGERID? Capsules are manufactured for Santarus, Inc., San Diego, CA 92130 by Norwich Pharmaceuticals, Inc., North Norwich, NY 13814.

ZEGERID? Powder for Oral Suspension is manufactured for Santarus, Inc. by Patheon Inc., Whitby, Ontario L1N 5Z5, Canada.

For more information call 1-888-778-0887

ZEGERID? is a registered trademark of Santarus, Inc.

This product is covered by one or more of the following: U.S. Patent Nos. 5,840,737; 6,489,346; 6,699,885; 6,780,882; 6,645,988, and 7,399,772 and additional patents pending.

? 2009 Santarus, Inc.

S0015F

维生素B片说明书

维生素B1片说明书【药品名称】通用名：维生素B1片英文名：Vitamin B1 Tablets 汉语拼音：Weishengsu B1 Pian 本品主要成分为：维生素B1。【性状】本品为白色片。【药理毒理】维生素B1结合三磷酸腺苷形成维生素B1焦磷酸盐(二磷酸硫胺，辅羧酶)，是碳水化合物代谢时所必需的辅酶；维生素B1能抑制胆碱酯酶的活性，缺乏时胆碱酯酶活性增强，乙酰胆碱水解加速，致神经冲动传导障碍，影响胃肠、心肌功能。【药代动力学】胃肠道吸收，主要在十二指肠。吸收不良综合征或饮酒过多能阻止吸收。吸收后分布于各组织，半衰期为0.35小时。肝内代谢，经肾排泄，正常人每日可吸收维生素B1 5～15mg。【适应症】 1.适用于维生素B1缺乏的预防和治疗，如维生素B1缺乏所致的脚气病或 Wernicke脑病。亦用于周围神经炎、消化不良等的辅助治疗。 2.全胃肠道外营养或摄入不足引起的营养不良时维生素B1的补充。 3.下列情况时维生素B1的需要量增加：妊娠或哺乳期、甲状腺功能亢进、烧伤、血液透析、长期慢性感染、发热、重体力劳动、吸收不良综合征伴肝胆系统疾病(肝功能损害、酒精中毒伴肝硬化)、小肠疾病(乳糜泻、热带口炎性腹泻、局限性肠炎、持续腹泻、回肠切除)及胃切除后。 4.大量维生素B1对下列遗传性酶缺陷病可改善症状：亚急性坏死性脑脊髓病 (Leigh病)、支链氨基酸病，乳酸性酸中毒和间歇性小脑共济失调。【用法用量】口服：

1.成人： (1)预防用量：推荐膳食中每日摄入维生素B1量，男性青年及成人1.2～1.5mg，女性青年及成人1～1.1mg，孕妇1.5mg，乳母1.6mg。正常膳食均可达上述需要量。 (2)治疗用量： ①成人脚气病(轻型或重型维持量)，一次5～10mg，一日3次；维生素B1缺乏症，一次5～10mg，一日3次，至症状改善； ②妊娠期由于维生素B1缺乏而致神经炎：一日5～10mg。 ③嗜酒而致维生素B1缺乏：一日40mg。 2.儿童： (1)预防用量：推荐膳食中每日摄入维生素B1量，出生至3岁婴儿0.3～0.7mg， 4～6岁小儿0.9mg，7～10岁小儿1mg。正常膳食均可达上述需要量。 (2)治疗用量： ①小儿脚气病(轻型)：一日10mg。 ②维生素B1缺乏症：一日10～50mg，分次服。【不良反应】维生素B1对正常肾功能者几乎无毒性。【禁忌症】【注意事项】 1.大剂量应用时，测定血清茶碱浓度可受到干扰，测定尿酸浓度可呈假性增高，尿胆原可呈假阳性。 2.治疗Wernicke脑病注射葡萄糖前，应先应用维生素B1。 3.维生素B1一般可由正常食物中摄取，较少发生单一维生素B1缺乏。如有缺乏症状表现，使用复合维生素B制剂较宜。

复方碳酸氢钠片制备

实训七复方碳酸氢钠片剂的制备一、实验目的 1、通过片剂制备，掌握湿法制粒压片的工艺过程。 2、会分析片剂处方的组成和各种辅料在压片过程中的作用。 3、熟悉片剂的质量检查项目。二、实验原理依据湿法制粒压片工艺要求，其制备过程为：处方拟定--物料准备与处理--粉碎--过筛--混合--制湿颗粒— 干燥--整粒--压片前处理--压片--质检--包装。三、实验药品与器材 1、药品：碳酸氢钠、淀粉、硬脂酸镁。 2、器材：托盘天平、烧杯、电炉、乳钵、玻棒、工业筛、烘箱、旋转压片机。四、实验内容复方碳酸氢钠片的制备处方：碳酸氢钠 20g （主药）淀粉 2g （崩解剂） 10%淀粉浆适量（黏合剂）硬脂酸镁适量0.7g（3％）（润滑剂）共制片剂 40片制法：（一）原辅料处理取碳酸氢钠与淀粉通过80目筛，置乳钵中研磨混匀。（二）制湿粒 1、10%淀粉浆制备称取淀粉5克，缓缓加入纯化水45ml，水浴加热搅拌至（沸）糊化，冷却，备用。 2、软材制备分次加入淀粉浆适量至碳酸氢钠乳钵中研匀使成软材。 3、湿颗粒制备将软材于16~18目筛上，用手掌轻压过筛使成湿颗粒。（三）干燥、整粒将湿颗粒置烘箱中，50℃以下烘干，干颗粒通过18~20目过筛整粒，加入3%硬脂酸镁混匀。（四）压片试压片、调片重、调压力，然后正式压片。（五）质量检查 1、外观。

2、含量测定。 3、重量差异。 4、崩解时限。 5、硬度。五、注意事项： 1、淀粉浆的制备采用水浴加热，且时间不宜过长。 2、加浆时温度不宜超过50℃，否则碳酸氢钠易分解。制软材时以“握之成团，轻压即散”为度。干燥时间约30分钟，每隔15分钟将颗粒轻轻翻动，使颗粒均匀干燥。六、思考题 1、简述片剂常用的赋形剂，各举例说明。 2、制备碳酸氢钠片时，如何避免碳酸氢钠分解。

注射用奥美拉唑钠说明书 (1)

注射用奥美拉唑钠说明书 Omeprazole Sodium for Injection 【适应症】作为当口服疗法不适用时下列病症的替代疗法：十二指肠溃疡、胃溃疡、反流性食管炎及Zollinger-Ellison综合症。 (1)20mg(2)40mg(以Cl17H l9N303S计) 【注意事项】 1。本品抑制胃酸分泌的作用强，时间长，故应用本品时不宜同时再服用其它抗酸剂或抑酸剂。为防止抑酸过度，在一般消化性溃疡等疾病，不建议大剂量长期应用(Zollinger-Ellison综合症患者除外)。 2．因本品能显着升高胃内pH值，可能影晌许多药物的吸收。 3．肾功能受损者不须调整剂量；肝功能受损者慎用，根据需要酌情减量。 4．治疗胃溃疡时应排除胃癌后才能使用本品，以免延误诊断和治疗。【孕妇和哺乳期妇女用药】尽管动物实验未发现本品对妊娠期和哺乳期有不良作用或对胎儿有毒性或致畸作用，但建议妊娠期和哺乳期妇女尽可能不用。【儿童用药】目前尚无儿童使用本品的经验。【老年用药】老年患者无需调整剂量。【不良反应】奥美拉唑的耐受性良好，不良反应多为轻度和可逆。下列不良反应为临床试验或常规使用中所报告。但在许多病例中与奥美拉唑治疗本身的因果关系尚未确定。下述不良反应中： “常见”是指发生率≥1/100；“不常见”是指发生率≥l／1000。但<1／100；“罕见”是指发生率<1／1000。常见中枢和外周神经系统：头痛；消化系统：腹泻、便秘、腹痛、恶心／呕吐和气胀。不常见中枢和外周神经系统：头晕、感觉异样、嗜睡、失眠和眩晕；肝脏：肝酶升高；皮肤：皮疹和(或)瘙痒、荨麻疹；其他：不适。罕见中枢和外周神经系统：可逆性精神错乱、激动、攻击性行为、抑郁和幻觉，多见于重症患者；内分泌系统：男子乳房女性化：消化系统：口干、口炎和胃肠道念珠菌感染；血液系统：白细胞减少、血小板减少、粒细胞缺乏症和各类血细胞减少：肝脏：脑病(见于先前有严重肝病患者)，肝炎或黄疸性肝炎、肝脏衰竭：肌肉与骨骼：关节痛、肌力减弱和肌痛：· 皮肤：光敏性、多形性红斑、Stevens-Johnson综合症、毒性表皮坏死(TEN)、脱发；其他：过敏反应，例如血管性水肿、发热、支气管痉挛、间质性肾炎和过敏性休克。出汗增多、外围水肿、视力模糊、味觉失常和低钠血症。曾有文献报道，个例重症患者接受高剂量奥美拉唑静脉注射后出现不可逆性视觉损伤。【禁忌】对本品过敏者禁用。【用法用量】

碳酸氢钠注射液资料8

资料项目8 制剂处方及工艺的研究资料和文献资料一、完整处方: 处方：2ml:0.1g 碳酸氢钠100g EDTA-2Na 0.4g 乳酸4g 注射用水2000ml 制成1000支二、制剂工艺: 1. 制备方法按处方量称取碳酸氢钠、EDTA-2Na和乳酸加入约1/2量注射用水，热搅拌使完全溶解，然后加注射用水至全量。取溶液测定pH值约7.5～8.5。加入0.1%活性炭搅拌均匀，搅拌约20分钟，过滤，除去活性炭，取滤后溶液测定含量应为标示量的90.0%～110.0%，调整分装机至规定装量，将滤液分装于安瓿瓶中，封口。于100℃灭菌30分钟。

2. 工艺流程图图一：小容量注射剂工艺流程图：

三、处方工艺选择依据 1. 规格的确定已上市的碳酸氢钠注射液的主要规格为：10ml：0.5g 、100ml：5g 和250ml：12.5g。因此我公司在不改变原有浓度的情况下特申报2ml：0.1g的碳酸氢钠注射液以方便临床使用。 2. 溶解性能根据碳酸氢钠原料药标准项下性状描述，碳酸氢钠在水中溶解，在乙醇中不溶。 3.处方筛选： 3.1 碳酸氢钠注射液：样品溶液经灭菌后有小白点的异样物，PH 值增加。此处方需要调整。 3.2 碳酸氢钠-EDTA-2Na：样品溶液经灭菌后虽没有小白点的异样物产生，但PH值仍增加。此处方仍需要调整。 3.3 碳酸氢钠-EDTA-2Na-乳酸：样品溶液经灭菌后即没有小白点的异样物产生，并且PH值也基本无变化。因此可以确定处方中的辅料为EDTA-2Na和乳酸。 4. 活性炭用量的确定按照确定的处方制备碳酸氢钠溶液，取适量分成4份，分别按重量体积比(w/v)0%、0.1%、0.2%、0.3%加入针用炭，70℃搅拌吸附约20分钟，过滤去炭，取续滤液测定含量，结果见表1。表1 活性炭用量对药物吸附作用的影响

碳酸氢钠片生产工艺规程

碳酸氢钠片生产工艺规程目录 1 概述 2 处方及依据 3 生产工艺流程及环境区域划分 4 生产工艺的操作要求 5 本产品工艺过程中所需SOP名称及要求 6 原辅材料、半成品和成品的质量标准和贮存注意事项 7 半成品检查方法及控制 8 需要验证的关键工序及其工艺验证的具体要求 9 包装袋、标签、包装箱的质量标准和检验方法及储存 10 物料平衡及技术经济指标计算 11 设备一览表及主要设备生产能力 12 生产技术安全及劳动保护 13 劳动组织与岗位定员 14 综合利用和环境保护附件1常用理化常数、换算表附件2 附页（供登记批准日期、文号等内容用）

一、目的：建立碳酸氢钠片生产工艺流程，用于该产品的生产指导。二、适用范围：适用于碳酸氢钠片产品的生产和管理。三、责任者：生产管理人员，各生产车间。四、内容： 1 概述 1.1 产品名称【通用名】：碳酸氢钠片【英文名】：Sodium Bicarbonate Tablets 【汉语拼音】: Tansuanqingna Pian 1.2 【性状】：本品为白色片 1.3 【作用与用途】：酸碱平衡调节药。用于酸血症，调节酸碱平衡；内服治疗胃肠卡他；碱化尿液。 1.4 【用法与用量】：内服：一次量，马15~60g，牛30~100g，羊5~10g，猪2~5g，犬0.5~2g。 1.5 【含量规格】：0.3g 1.6 【包装规格】：0.3g/片×100片/袋×20袋/中包×10中包/箱 1.7 【有效期】：二年 1.8 【贮藏】：密封，干燥处保存 2 处方和依据碳酸氢钠50kg 淀粉5kg 硬脂酸镁0.15kg 10%淀粉浆适量处方依据：《中国兽药典》2010年版一部

2.奥美拉唑碳酸氢钠胶囊和混悬剂Zegerid-FDA说明书

HIGHLIGHTS 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 Initial U.S. Approval: 2004 ----------------------------RECENT MAJOR CHANGES--------------------------Warnings and Precautions, 11/2012 Clostridium difjicile associated diarrhea (5.4) Warnings and Precautions, 11/2012 Interaction with clopidogrel (5.5) Warnings and Precautions, 11/2012 Concomitant Use of ZEGERID with St. John’s Wort or Rifampin (5.8) Warnings and Precautions,Interactions with Diagnostic 11/2012 Investigations for Neuroendocrine Tumors (5.9) Warnings and Precautions, 04/2012 Concomitant Use of Zegerid with Methotrexate (5.10) ------------------------INDICATIONS 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) ----------------------DOSAGE AND ADMINISTRATION-----------------------? Short-Term Treatment of Active DuodenalUlcer: 20 mg oncedaily for 4 weeks (some patients may requirean 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) ---------------------DOSAGE FORMS AND STRENGTHS----------------------? ZEGERID is available as a capsule and as a powder for oral suspension in 20 mg and 40 mg strengths (3) -------------------------------CONTRAINDICATIONS-----------------------------? Known hypersensitivity to any components of the formulation (4) -----------------------WARNINGS 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) ? Buffer Content: contains sodium bicarbonate (5.3) ? PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.4) ? Avoid concomitant use of Zegerid with clopidogrel (5.5) ? 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. (5.6) ? Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.7) ? Avoid concomitant use of Zegerid with St John’s Wort or rifampin due to the potential reduction in omeprazole concentrations (5.8, 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. (5.9, 12.2) ------------------------------ADVERSE REACTIONS-------------------------------Most common adverse reactions (incidence ≥ 2%) are: Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence (6) To report SUSPECTED ADVERSE REACTIONS, contact Santarus Ienc. at 1-888-778-0887 or FDA at 1-800-FDA-1088 or https://www.360docs.net/doc/718385008.html,/medwatch. ------------------------------DRUG INTERACTIONS-------------------------------? Drugs for which gastric pH can affect bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, and digoxin): ZEGERID may interfere with absorption due to inhibition of gastric acid secretion (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) -----------------------USE 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) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 11/2012

临床配液

生理盐水与葡萄糖作为溶媒的运用区别 (医学精英网)来源：执业医师考试的日志一：用糖水还是用盐水要根据病人的具体情况而定. 1:根据病人的原发病及其并发症而定：（1 ）如果病人有高血压,冠心病,及心功能不好,应减少盐水的摄入,以减轻心脏负担. （2）如果病人有糖尿病但心肾功能尚可,可以用盐水,但用糖时可加胰岛素兑调. （3）.如病人肾功能不好,要减少钠水的摄入,减轻钠水储溜. 2:根据病人的化验结果. （1）如电解质结果.看是否有低钠血症,则给予盐水,反之用糖. （2）根据心肌酶等评测心功能,来决定盐糖的选择. 3:配液有的药物溶于糖或盐其效能会好点,这要根据药物说明书选则糖盐. 4:如病人休克,应先给于盐水补充血容量再给于糖补能. 5:盐水主要用于电解质的调节而糖主要作为能量选用时要首先想到这点. 总之,选择时要慎重,尤其是呼吸科,老年病人多,不同程度存在心功能不好,糖尿病,在选盐时要谨慎,选糖时考虑是否加用胰岛素。二：溶媒的选择主要还是从抗生素的稳定性方面考虑 1：溶媒的选择主要还是从抗生素的稳定性方面考虑的。在制剂中，葡萄糖在生产过程中需加入盐酸，成品溶液P H多为3左右，而生理盐水稍高，一般为4～5。β—内酰胺类在近中性（PH=6～7）溶液中较为稳定，酸性或碱性溶液均易使β—内酰胺环开环，失去抗菌活性，故应选盐做溶媒。大环内酯类抗生素在碱性条件下抗菌效能比酸性条件下可增强10多倍（有相关的研究报道），故建议选盐做溶媒，或在溶媒中加入碳酸氢钠提高PH值。 2.溶媒使用的量一般以说明书规定的最低量控制。对于半衰期短的药物，如青霉素，我在儿科临床中就有看到溶于500ml糖溶液，输了2个多小时，前面的药物都代谢了，还没输完，根本达不到有效药物浓度。现在大多是使用100ml+抗生素，或许是治疗习惯，这样效率比较高。 .为什么抗生素不静推而要静点?第一是因为药物代谢动力学的原因(房室模型,表观分布等有关),二是因为油溶液及水(油)混悬液禁用于静注(抗生素多为水混悬液),因为可引起血管栓塞的危险.这在11版新编药物学上有明确指出. 2.用盐水还是糖水配伍抗生素的问题:其实这是和药物自身理化性质有关了,通常头孢类,青霉素类的抗生素在盐水的PH值中比较稳定,在外界配好后12小时内静滴都可以,但是在葡萄糖这类大分子物质中,抗生素会络合,稳定性下降. 而合成类抗生素如甲硝唑,奎诺酮类等由于其分子结构的特定性,5%的葡萄糖溶液比生理盐水形状更稳定,有关这个问题的详细解释可以请教药学板块的战友. 3.关于溶媒量的问题为什么用100,不用250?其实这个就是习惯问题了,没有绝对要求的,但是对于那些需要限制水输入量的患者(肝硬化腹水,心衰),以及需要迅速把药输完提高血药浓度的,应该用100ml液体配伍. 4：主张使用生理盐水，主要还是从抗生素的稳定性方面考虑的。以青霉素类为例，它们在近中性（PH=6～7）溶液中较为稳定，酸性或碱性溶液均使之分解加速，应用时最好用注射用水或等渗氯化钠注射液溶解青霉素类。溶于葡萄糖液（PH=3.5～5.5）中可有一定程度的分解。青霉素类在碱性溶液中分解极快。因此，严禁将碱性药液（碳酸氢钠、氨茶碱等）与其配伍。原则按药品说明书上明确规定配液要求的配制，一般进口药物说明书比较详细，战友可以搜索一些！喹诺酮类，如左氧氟沙星，特别是培氟沙星，应该用糖水配。培氟沙星不能见氯离子，否则会形成沉淀。氨苄西林要用生理盐水不能用葡萄糖。具体问题具体分析

痛风患者不易长期服用碳酸氢钠片

痛风患者不易长期服用碳酸氢钠片发表时间：2019-07-26T15:06:36.973Z 来源：《中国结合医学杂志》2019年5期作者：张月荣[导读] 痛风问题主要是因为单钠尿酸盐沉积而导致的关节病，其中痛风与嘌呤代谢和尿酸排泄减少具有密切的关联性，痛风的主要生化基础是高尿酸血症，在我们日常生活中，正常人每日约产生750毫克的尿酸，但是有80%左右为内源性尿酸，25%外源性尿酸，通过将尿酸排入到尿酸代谢池，能够保证每日的代谢成尿酸，有60%待解，并且，有1/3经过肠道分解，剩余的2/3，经过肾脏进行排泄，这样就能够保证人体内的尿酸平均水平。四川省都江堰人民医院四川成都 611830 痛风问题主要是因为单钠尿酸盐沉积而导致的关节病，其中痛风与嘌呤代谢和尿酸排泄减少具有密切的关联性，痛风的主要生化基础是高尿酸血症，在我们日常生活中，正常人每日约产生750毫克的尿酸，但是有80%左右为内源性尿酸，25%外源性尿酸，通过将尿酸排入到尿酸代谢池，能够保证每日的代谢成尿酸，有60%待解，并且，有1/3经过肠道分解，剩余的2/3，经过肾脏进行排泄，这样就能够保证人体内的尿酸平均水平。由于许多的患者，经常会大量饮酒或者吃飘零比较高的食物，例如在喝酒时吃海鲜很容易引起痛风问题。痛风包括原发性痛风和继发性痛风，其中原发性痛风具有一定的遗传性，但是有痛风家族史者在临床医学中仅为10%～20%左右，其中大多数都是因为尿酸生成过高而导致的原发性高尿酸血症，主要的原因就是患者自身嘌呤代谢酶缺陷，以及缺乏磷酸核糖焦磷酸盐。还有许多患者是因为肾脏尿酸排泄不足而导致尿酸血症，继发性痛风则是指治疗其他疾病过程中产生的痛风问题，例如白血病，淋巴瘤以及多发性骨髓瘤等，这些都可能导致体内血胞繁殖速度增加，而导致尿酸产生过多的问题，此外在药物中如果大量服用乙胺丁醇，呋塞米，阿司匹林或者烟酸等，也有可能引起尿酸症。痛风主要病发于中年男性，而女性痛风的几率仅为5%，但是随着近些年来人们的生活品质得到增强，痛风的发生已经逐渐呈现年轻化的发展趋势。痛风在发作时包括间歇性发作期，慢性期，其中大多数患者发生痛风并没有明显的征兆，仅有关节突然刺痛的情况，经常会因为深夜关节痛而惊醒，并且疼痛加剧，在12小时左右达到高峰，在痛风发生之后，关节以及周围组织会出现红肿热痛，乃至步行功能受到限制，患者的足背足跟以及关节等都可能出现发热，红肿的现象，在痛风持续发作之后会自行消除，但是遗留局部的皮肤会出现明显的色素沉着，在进入后续无症状间歇期，经过数月数年或者数10年都会病发，多数患者在短时间内会频繁病发，如果并发越频繁，则受累关节也就越多，导致痛风的症状越来越明显，当皮下痛风石以及慢性痛风石关节炎，大量积累之后，会造成明显的痛风变形问题，痛风关节内沉积的痛风石也会导致关节骨质破坏，或者周围发生组织纤维化。由于关节肿痛畸形，甚至引起功能障碍等问题。在痛风治疗的过程中，很多的痛风患者往往在发病时会痛下决心，坚决抵制喝酒或者吃高漂流的食物，但是在病好之后，却好了伤疤忘了疼，往往在应酬的过程中大量的饮酒，这样长此以往很容易造成体内的尿酸过高，对肾脏血管和胰岛都会产生危害，在痛风发作时不要使劲揉搓，可以通过运用冷敷的方式进行有效控制，并且要尽可能的减少患者运动，否则会导致血液循环速度加快，造成病人的疼痛感增加，在肾功能正常的情况下可以采用秋水仙碱进行治疗，但是不能够加降尿酸的药物，在急性期可以用降尿酸的药物，确保体内的尿酸快速排除。通过服用碳酸氢钠，可以有效的碱化尿液，确保尿酸不能够在尿液中形成结晶，而且也能够顺利的排出肾脏，避免尿酸沉积过多而导致肾脏出现损害。但是碳酸氢钠很容易在胃中与胃酸发生反应，而释放大量的二氧化碳，导致患者的胃部气量过多，出现腹胀等问题，如果长时间大量服用碳酸氢钠，甚至会引起碱血症以及电解质紊乱，如果患者肾功能不全，会出现水肿以及充血性心力衰竭等问题，必须要及时的停止碳酸氢钠片，否则很容易加重病情。尽管碳酸氢钠就是小苏打片，但是如果长时间的服用会影响胃酸，所以患者可以适当的间歇性吃，但不能够长期吃。因为任何药物，都不可能长期服用，为此必须要积极在医生的临床指导之下正规用药。为了能够有效缓解患者痛风的问题，可以积极的采用药物治疗和饮食治疗，避免吃含嘌呤较高的食物，例如动物肝脏，海鲜，蘑菇以及肉汤的，同时要多喝水，多吃青菜和水果，加强体质运动，如果症状得到缓解，只要尿酸不高就可以停药，但是在日常生活中还需要注重饮食控制。超重患者应降低体重，但应避免高蛋白及低碳水化合物饮食；鼓励进食脱脂奶、酸奶、大豆、植物蛋白及樱桃；应限制红肉及含嘌呤高的食物。肝脏、牡蛎及酵母提取物应严格控制，应限制过量蛋白质摄取。痛风及有尿酸石病史者应鼓励每天饮水多于2000ml，避免脱水。对于反复痛风石形成的患者应给予枸橼酸钾碱化尿液；酒精摄取量应限制在每周少于21个单位（男）或14个单位（女），应鼓励每周3天不饮酒，啤酒应尽量避免，抬高受累关节及避免暴露在较凉的环境中，冰袋及床上支架对治疗有帮助。应避免剧烈运动或关节损伤，但鼓励适当运动。对复发性、间歇期及慢性痛风的治疗血尿酸水平应维持在300mmol/L以下；如果1年内第2次发作或2次以上发作，应给予简单的降尿酸药，有痛风结节、伴肾功能不全、有尿路结石或需利尿剂继续治疗的患者应给予降尿酸治疗；在炎症控制1~2周后开始降尿酸药治疗。无合并症的痛风患者的长期治疗所使用的别嘌呤醇从50-100mg/d开始，每数周增加50~100mg，根据肾功能的情况调整剂量，最终达到治疗目标（尿酸<300mmol/L），别嘌呤醇最大剂量900mg/d。在尿酸分泌很低和对别嘌呤抵抗或不耐受的患者，可使用促尿酸排泄药作为二线药；苯溴马龙（50-200mg/d）用于轻中度肾功能不全的患者。开始用别嘌呤醇或促尿酸排泄的药时（为防止痛风发作），应同时加用秋水仙碱0.5mg，每日2次，可持续应用最长达6个月。对于不能耐受秋水仙碱的患者可用非甾类抗炎药，但不应超过6周。按正常规律来说，如果你不降尿酸，第一次发作到第二次可能相对较长，但以后间隔会逐渐缩短，慢慢地就没有中间的间隔了。等那时候，可能你的关节已经出现破坏，肾脏或血管出现了不可逆的病变。特别是合并有其他危险因素，如三高或本身肾功能不全的病人，还是主张服降尿酸的药物。虽然我们是这么建议的，但不少痛风患者觉得平时没症状，吃不吃药都无所谓，依从性并不好，一些人只在每次进食大量嘌呤食物之后才想起要吃药。其实，从科学治疗的角度来说，我们并不建议这么做。当然，一些患者也会这么问，说这降尿酸的药物要吃多久。基本上，血尿酸通过药物治疗很快就下去了，但要使关节周围沉积下来多余的尿酸，或者痛风石有所缓解或减少或完全消失，需要一段较长的时间，一般而言，药物治疗半年以上才能把体内多余的尿酸尽量排出去。

奥美拉唑碳酸氢钠FDA说明书

Zegerid (omeprazole) Powder for Oral Suspension DESCRIPTION The active ingredient in Zegerid (omeprazole) powder for oral suspension, 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 Powder for Oral Suspension is supplied in unit dose packets as an immediate release formulation to be constituted with water for oral administration. Each packet contains 20 mg of omeprazole and the following excipients: sodium bicarbonate, sucrose, sucralose, xanthan gum, xylitol, and flavorings. CLINICAL PHARMACOLOGY Omeprazole is acid labile and thus rapidly degraded by gastric acid. Zegerid Powder for Oral Suspension is an immediate-release formulation that contains sodium bicarbonate to protect omeprazole from acid degradation. Pharmacokinetics: Absorption

碳酸氢钠(小苏打)

碳酸氢钠碳酸氢钠的结构式编辑本段

中文名称:碳酸氢钠、重碳酸钠、小苏打英文名称:Carbonicacidmonosodiumsalt sodiumbicarbonate bakingsoda bicarbonatedesodium bicarbonateofsoda 是指有别于工业用碱的纯碱(碳酸钠)和小苏打(碳酸氢钠)，小苏打是由纯碱的溶液或结晶吸收二氧化碳之后的制成品，二者本制上没有区别。所以，小苏打在有些地方也被称作食用碱（粉末状）。小苏打呈固体状态，圆形，色洁白，易溶于水。编辑本段物理性质碳酸氢钠为白色晶体，或不透明单斜晶系细微结晶。比重2.15g。无臭、味咸，可溶于水，微溶于乙醇。其水溶液因水解而呈微碱性，受热易分解，在65℃以上迅速分解，在270℃时完全失去二氧化碳，在干燥空气中无变化，在潮湿空气中缓慢分解。溶解度：7.8g，18 °C；16.0g，60°C 。编辑本段化学性质与HCl反应：NaHCO?+HCl ==== NaCl + H?O + CO?↑ 与NaOH反应：NaHCO?+NaOH ==== Na?CO?+ H?O 与AlCl?双水解：3NaHCO?+ AlCl?==== Al(OH)?↓+ 3CO?+ 3NaCl 与Al?(SO4)?双水解：Al?(SO4)?+6NaHCO?==3Na?SO4+2Al 碳酸氢钠 (OH)?↓+6CO?↑

与CaCl?反应：2NaHCO?+ CaCl?==== Ca(HCO?)?+ 2NaCl 与氢氧化钙反应：要分过量和少量。少量：NaHCO?+ Ca(OH)?==== CaCO?+ NaOH + H?O 过量：2NaHCO?+ Ca(OH)?==== Na?CO?+ CaCO?+ 2H?O 受热分解：2NaHCO?==△== Na?CO?+ H?O + CO?↑ 编辑本段用途灭火器碳酸氢钠用作食品工业的发酵剂、汽水和冷饮中二氧化碳的发生剂、黄油的保存剂。可直接作为制药工业的原料，用于治疗胃酸过多。还可用于电影制片、鞣革、选矿、冶炼、金属热处理，以及用于纤维、橡胶工业等。同时用作羊毛的洗涤剂、泡沫灭火剂，以及用于农业浸种等。食品工业中一种应用最广泛的疏松剂，用于生产饼干、糕点、馒头、面包等，是汽水饮料中二氧化碳的发生剂；可与明矾复合为碱性发酵粉，也可与纯碱复合为民用石碱；还可用作黄油保存剂。消防器材中用于生产酸碱灭火机和泡沫灭火机。橡胶工业利用其与明矾、H发孔剂配合起均匀发孔的作用用于橡胶、海棉生产。冶金工业用作浇铸钢锭的助熔剂。机械工业用作铸钢(翻砂)砂型的成型助剂。印染工业用作染色印花的固色剂，酸碱缓冲剂，织物染整的后处理剂。染色中加入小苏打可以防止纱筒产生色花。医药工业用作制酸剂的原料。医药用途碳酸氢钠

碳酸氢钠注射液说明书

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