Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE ZEGERID is a proton pump inhibitor (PPI) 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) 1.1 Duodenal Ulcer ZEGERID (omeprazole/sodium bicarbonate) is indicated for short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. [See Clinical Studies (14.1).] 1.2 Gastric Ulcer ZEGERID is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer. [See Clinical Studies (14.2).] 1.3 Treatment of Gastroesophageal Reflux Disease (GERD) Symptomatic GERD ZEGERID is indicated for the treatment of heartburn and other symptoms associated with GERD for up to 4 weeks. [See Clinical Studies (14.3).] Erosive Esophagitis ZEGERID is indicated for the short-term treatment (4-8 weeks) of erosive esophagitis which has been diagnosed by endoscopy. The efficacy of ZEGERID used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, it may be helpful to give up to an additional 4 weeks of treatment. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), an 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 (40 mg 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 (14.5).]

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Advisory information

contraindications
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, acute interstitial nephritis, and urticaria. [See Adverse Reactions (6).] •Known hypersensitivity to any components of the formulation (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: •Acute Interstitial Nephritis [see Warnings and Precautions (5.2)] • Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.4)] •Bone Fracture [see Warnings and Precautions (5.5)] •Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)] •Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.8)] •Hypomagnesemia [see Warnings and Precautions (5.9)] •Fundic Gland Polyps [see Warnings and Precautions (5.13)] Most common adverse reactions (incidence ≥2%) are: headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 (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. Table 3: Incidence of Adverse Reactions ≥1% Causal Relationship Not Assessed 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. Table 4: Number (%) of Critically Ill Patients with Frequently Occurring (≥3%) Adverse Events by Body System and Preferred Term ZEGERID® (N=178) Cimetidine (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) 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 DISORDERSClinically significant upper gastrointestinal bleeding was considered a serious adverse event but it is not included in this table. 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) Hyperglycemia NOS 19 (10.7) 21 (11.6) Hyperkalemia 4 (2.2) 6 (3.3) Hypernatremia 3 (1.7) 9 (5.0) Hypocalcemia 11 (6.2) 10 (5.5) Hypoglycemia NOS 6 (3.4) 8 (4.4) Hypokalemia 22 (12.4) 24 (13.3) Hypomagnesemia 18 (10.1) 18 (9.9) Hyponatremia 7 (3.9) 5 (2.8) Hypophosphatemia 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) 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 reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their 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, and systemic lupus erythematosus. 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, abdominal swelling and fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), ᵞ-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy. Infections and Infestations: Clostridium difficile-associated diarrhea. Metabolism and Nutritional Disorders: Hyponatremia, hypoglycemia, hypomagnesemia, and weight gain. Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain. Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia. Respiratory: Epistaxis, pharyngeal pain. Skin: Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus 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, leukocytosis, 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.

Usage information

Dosing and administration
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 (1,680 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 (1,100 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 weeksMost patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. [See Clinical Studies (14.1).] For additional information, [see Indications and Usage (1)]. Benign Gastric Ulcer 40 mg Once daily for 4-8 weeks Controlled studies do not extend beyond 12 months. [See Clinical Studies (14).] 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. •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: (40 mg oral suspension only) 40 mg initially followed by 40 mg 6-8 hours later and 40 mg daily thereafter for 14 days (2) * studied for 12 months
Use in special populations
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) 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies on the use of ZEGERID in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on body surface area basis for a 60 kg person). However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 33.6 times an oral human dose of 40 mg (see Animal Data). Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, ZEGERID should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Register, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single-dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.36 to 33.6 times an oral human dose of 40 mg on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.36 to 33.6 times an oral human dose of 40 mg on a body surface area basis). Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with the S-enantiomer, esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg of esomeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 16.8 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses of esomeprazole magnesium equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational Day 7 through weaning on postnatal Day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses of esomeprazole magnesium equal to or greater than 138 mg/kg/day (about 33.6 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. 8.3 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. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg on a body surface area basis. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth. [See Nonclinical Toxicology (13.2).] 8.5 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. 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).]
Pregnancy and lactation
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.

Interactions

7 DRUG INTERACTIONS •May interfere with drugs for which gastric pH can affect bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, erlotinib, digoxin, and mycophenolate mofetil. (7.1) •Drugs Metabolized by Cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): ZEGERID can prolong their elimination. Monitor to determine the need for possible dose adjustments when taken with ZEGERID. (7.2) •Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. (7.2) •Voriconazole: May increase plasma levels of omeprazole. (7.2) •Saquinavir: ZEGERID increases plasma levels of saquinavir. (7.3) •ZEGERID may reduce plasma levels of atazanavir and nelfinavir. (7.3) •Clopidogrel: ZEGERID decreases exposure to the active metabolite of clopidogrel. (7.5) •Tacrolimus: ZEGERID may increase serum levels of tacrolimus. (7.6) 7.1 Drugs for Which Gastric pH Can Affect Bioavailability Due to its effects on gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Coadministration of digoxin with ZEGERID is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with ZEGERID. Coadministration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving ZEGERID and MMF. Use ZEGERID with caution in transplant patients receiving MMF. [See Clinical Pharmacology (12.3).] 7.2 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 international normalized ratio (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 P450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with ZEGERID. Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. When voriconazole (400 mg every 12 hours for one day, then 200 mg for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a crossover study in 12 healthy male subjects, St. John’s wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s wort or rifampin with omeprazole. 7.3 Antiretroviral Agents Concomitant administration of atazanavir and proton pump inhibitors is not recommended. Coadministration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect. Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg, daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Increased Concentration of Saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in Cmax by 75% and in Cmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily coadministered days 11 to 15. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. 7.4 Combination Therapy with Clarithromycin Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interaction [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for coadministration with certain drugs [see Contraindications in prescribing information for clarithromycin]. 7.5 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. Avoid concomitant administration of ZEGERID with clopidogrel. When using ZEGERID, consider use of alternative antiplatelet therapy. [See Clinical Pharmacology (12.3).] 7.6 Tacrolimus Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus. 7.7 Interactions with Investigations of Neuroendocrine Tumors Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. [See Clinical Pharmacology (12).] 7.8 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted. [See Warnings and Precautions (5.12).]

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Category Value
Authorisation number NDA021636
Agency product number 8MDF5V39QO
Orphan designation No
Product NDC 68012-052,68012-104,68012-102,68012-054
Date Last Revised 13-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 616541
Marketing authorisation holder Santarus, Inc..