Dosage Form: capsule; powder, for suspension
FULL PRESCRIBING INFORMATION
Indications and Usage for Zegerid
Duodenal Ulcer
Zegerid (omeprazole/sodium bicarbonate) is indicated for short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. [See Clinical Studies (14.1)]
Gastric Ulcer
Zegerid is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer. [See Clinical Studies (14.2)]
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)]
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)]
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)]
Zegerid 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.
* 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)] | ||
| 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 | 40 mg initially followed by 40 mg 6-8 hours later and 40 mg daily thereafter for 14 days** |
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.
Use with clopidogrel
Avoid concomitant use of clopidogrel and omeprazole. Coadministration of clopidogrel with 80 mg omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart [see Warnings and Precautions (5.6) and Drug Interactions (7)].
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.
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.
Warnings and Precautions
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.
Atrophic gastritis
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.
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.
Bone Fracture
Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. [See Dosage and Administration (2) and Adverse Reactions (6.2)]
Diminished Anti-platelet Activity of clopidogrel due to Impaired CYP2C19 Function by Omeprazole
Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Avoid concomitant use of clopidogrel and omeprazole. Co-administration of clopidogrel with 80 mg omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart [see Drug Interactions (7)].
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Adverse Reactions (6.2)]
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In the U.S. clinical trial population of 465 patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Numbers in parentheses indicate percentages of the adverse reactions considered by investigators as possibly, probably or definitely related to the drug.
| Omeprazole (n = 465) | Placebo (n = 64) | Ranitidine (n = 195) | |
| Headache | 6.9 (2.4) | 6.3 | 7.7 (2.6) |
| Diarrhea | 3.0 (1.9) | 3.1 (1.6) | 2.1 (0.5) |
| Abdominal Pain | 2.4 (0.4) | 3.1 | 2.1 |
| Nausea | 2.2 (0.9) | 3.1 | 4.1 (0.5) |
| URI | 1.9 | 1.6 | 2.6 |
| Dizziness | 1.5 (0.6) | 0.0 | 2.6 (1.0) |
| Vomiting | 1.5 (0.4) | 4.7 | 1.5 (0.5) |
| Rash | 1.5 (1.1) | 0.0 | 0.0 |
| Constipation | 1.1 (0.9) | 0.0 | 0.0 |
| Cough | 1.1 | 0.0 | 1.5 |
| Asthenia | 1.1 (0.2) | 1.6 (1.6) | 1.5 (1.0) |
| 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.
| Omeprazole (n = 2631) | Placebo (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.
* Clinically significant upper gastrointestinal bleeding was considered a serious adverse event but it is not included in this table. | ||
NOS = Not otherwise specified. | ||
| Zegerid® (N=178) | Cimetidine (N=181) | |
| MedDRA Body System Preferred Term | All AEs n (%) | All AEs n (%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS | ||
| Anemia NOS | 14 (7.9) | 14 (7.7) |
| Anemia NOS Aggravated | 4 (2.2) | 7 (3.9) |
| Thrombocytopenia | 18 (10.1) | 11 (6.1) |
| CARDIAC DISORDERS | ||
| Atrial Fibrillation | 11 (6.2) | 7 (3.9) |
| Bradycardia NOS | 7 (3.9) | 5 (2.8) |
| Supraventricular Tachycardia | 6 (3.4) | 2 (1.1) |
| Tachycardia NOS | 6 (3.4) | 6 (3.3) |
| Ventricular Tachycardia | 8 (4.5) | 6 (3.3) |
| GASTROINTESTINAL DISORDERS * | ||
| 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) |
| INFECTIONS AND INFESTATIONS | ||
| Candidal Infection NOS | 3 (1.7) | 7 (3.9) |
| Oral Candidiasis | 7 (3.9) | 1 (0.6) |
| Sepsis NOS | 9 (5.1) | 9 (5.0) |
| Urinary Tract Infection NOS | 4 (2.2) | 6 (3.3) |
| INVESTIGATIONS | ||
| Liver Function Tests NOS Abnormal | 3 (1.7) | 6 (3.3) |
| METABOLISM AND NUTRITION DISORDERS | ||
| Fluid Overload | 9 (5.1) | 14 (7.7) |
| Hyperglycaemia NOS | 19 (10.7) | 21 (11.6) |
| Hyperkalaemia | 4 (2.2) | 6 (3.3) |
| Hypernatraemia | 3 (1.7) | 9 (5.0) |
| Hypocalcaemia | 11 (6.2) | 10 (5.5) |
| Hypoglycaemia NOS | 6 (3.4) | 8 (4.4) |
| Hypokalaemia | 22 (12.4) | 24 (13.3) |
| Hypomagnesaemia | 18 (10.1) | 18 (9.9) |
| Hyponatraemia | 7 (3.9) | 5 (2.8) |
| Hypophosphataemia | 11 (6.2) | 7 (3.9) |
| PSYCHIATRIC DISORDERS | ||
| Agitation | 6 (3.4) | 16 (8.8) |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | ||
| Acute Respiratory Distress Syndrome | 6 (3.4) | 7 (3.9) |
| Nosocomial Pneumonia | 20 (11.2) | 17 (9.4) |
| Pneumothorax NOS | 1 (0.6) | 8 (4.4) |
| Respiratory Failure | 3 (1.7) | 6 (3.3) |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||
| Decubitus Ulcer | 6 (3.4) | 5 (2.8) |
| Rash NOS | 10 (5.6) | 11 (6.1) |
| VASCULAR DISORDERS | ||
| Hypertension NOS | 14 (7.9) | 6 (3.3) |
| Hypotension NOS | 17 (9.6) | 12 (6.6) |
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of omeprazole. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.
Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise.
Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis and abdominal swelling. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.
Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), γ-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.
Metabolism and Nutritional Disorders: Hyponatremia, hypoglycemia, hypomagnesemia, and weight gain.
Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.
Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.
Respiratory: Epistaxis, pharyngeal pain.
Skin: Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens-Johnson syndrome, and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.
Special Senses: Tinnitus, taste perversion.
Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis and double vision.
Urogenital: Interstitial nephritis (some with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.
Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leucocytosis, and hemolytic anemia have been reported.
The incidence of clinical adverse experiences in patients greater than 65 years of age was similar to that in patients 65 years of age or less.
Additional adverse reactions that could be caused by sodium bicarbonate include metabolic alkalosis, seizures, and tetany.
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, iron salts, and digoxin). In the clinical efficacy trials, antacids were used concomitantly with the administration of omeprazole.
Drugs metabolized by cytochrome P450 (CYP)
Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time.
Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P-450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with Zegerid.
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required.. When voriconazole (400 mg every 12 hours for one day, then 200 mg for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole.
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 reduce its therapeutic effect.
Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg, daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. 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.
1Mean ± (μg/g) | ||
| 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) |
Clopidogrel
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Warnings and Precautions (5.6)].
In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. The active metabolite of clopidogrel selectively and irreversibly inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor, thereby inhibiting platelet aggregation. The mean inhibition of platelet aggregation at 5 mcM ADP was diminished by 39% (Day 1) and 21% (Day 5) when clopidogrel and omeprazole were administered together.
In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions (5.6)].
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.
USE IN SPECIFIC POPULATIONS
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.
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
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