Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole.
ZEGERID™ contains 460 mg sodium per dose in the form of sodium bicarbonate. This should be taken into consideration for patients on a sodium-restricted diet.
ZEGERID™ contains 1680 mg (20 mEq) of sodium bicarbonate. Sodium bicarbonate is contraindicated in patients with metabolic alkalosis and hypocalcemia. Sodium bicarbonate should be used with caution in patients with Bartter's syndrome, hypokalemia, and respiratory alkalosis. Long-term administration of bicarbonate with calcium or milk can cause milk-alkali syndrome.
INFORMATION FOR PATIENTS
ZEGERID™ is supplied as a powder for oral suspension. It should be taken on an empty stomach at least 1 hour prior to a meal.
ZEGERID™ is available as 20 mg single-dose packets. Directions for use: Empty packet contents into a small cup containing 2 tablespoons of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and drink immediately. Refill cup with water and drink.
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 healthy 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™.
Because of its profound and long-lasting 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 bioavaila-bility (e.g., ketoconazole, ampicillin esters, and iron salts). In the clinical trials, antacids were used concomitantly with the administration of omeprazole.
Co-administration of omeprazole and clarithromycin have resulted in increases of plasma levels of omeprazole, clarithromycin, and 14-hydroxy-clarithromycin (see also CLINICAL PHARMACOLOGY, Pharmacokinetics).
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 (about 0.7 to 57 times the human dose of 20 mg per 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 (about 5.7 times the human dose of 20 mg per 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 vs 10% controls). By the second year the difference between treated and control rats was much smaller
(46% vs 26%) but still showed more hyperplasia in the treated group. 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 0.2 to 6.5 times the human dose of 20 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 57 times the human dose of 20 mg per 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 Salmonella typhimurium assay, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138.0 mg/kg/day (about 56 times the human dose of 20 mg per day, based on body surface area) was found to have no effect on fertility and reproductive performance.
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 vs. 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).
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. 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). 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). 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.
Teratology studies conducted in pregnant rats at omeprazole doses up to 138 mg/kg/day (about 56 times the human dose of 20 mg/day, based on body surface area) and in pregnant rabbits at doses up to 69 mg/kg/day (about 56 times the human dose of 20 mg per 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 69.1 mg/kg/day (about 5.6 to 56 times the human dose of 20 mg per 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 5.6 to 56 times the human dose of 20 mg per day, based on body surface area).
Chronic use of sodium bicarbonate may lead to systemic alkalosis and increased sodium intake can produce edema and weight increase. 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, omeprazole should be used during pregnancy only if the potential benefit to pregnant women justifies the potential risk to the fetus.
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. In rats, omeprazole administration during late gestation and lactation at doses of 13.8 to 138 mg/kg/day (about 5.6 to 56 times the human dose of 20 mg per day, based on body surface area) resulted in decreased weight gain in pups. 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 whether 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.
There are no adequate and well-controlled studies in pediatric patients with ZEGERID™.
Omeprazole was administered to over 2000 elderly individuals (>/= [nbsp ]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 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 the same as that in nonelderly, healthy subjects taking ZEGERID™. However, no dosage adjustment is necessary in the elderly. (See CLINICAL PHARMACOLOGY.)