These highlights do not include all the information needed to use OMEPRAZOLE DELAYED-RELEASE

CAPSULES safely and effectively. See full prescribing information for OMEPRAZOLE DELAYED-RELEASE CAPSULES. OMEPRAZOLE delayed-release capsules, for oral use INITIAL U.S. APPROVAL: 1989 · A-S Medication Solutions

Dosage Form

CAPSULES safely and effectively. See full prescribing information for OMEPRAZOLE DELAYED-RELEASE CAPSULES. OMEPRAZOLE delayed-release capsules, for oral use INITIAL U.S. APPROVAL: 1989

Manufacturer

A-S Medication Solutions

Important Safety Information

This medication contains important usage instructions, warnings, and side effect information that you should review before use.

Full label on DailyMed PDF Full label (ZIP)

Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with Omeprazole delayed-release capsules and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table 3 Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics

Antiretrovirals
Clinical Impact	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see clinical Pharmacology (12.3)].
There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention	Rilpivirine-containing products: Concomitant use with omeprazole delayed-release capsule is contraindicated [see Contraindications (4)] .
Atazanavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for nelfinavir.
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. 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.
Intervention	Avoid concomitant use with omeprazole delayed-release capsules. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)] .
Intervention	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact	Potential for increased exposure of phenytoin.
Intervention	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact	Increased exposure of diazepam [see Clinical Pharmacology (12.3)] .
Intervention	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole delayed-release capsules and MMF. Use omeprazole delayed-release capsules with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.1), Clinical Pharmacology (12.2)] .
Intervention	Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention	Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)] .
False Positive Urine Tests for THC
Clinical Impact	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole delayed-release capsules.

Table 4 Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs

CYP2C19 or CYP3A4 Inducers
Clinical Impact	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention	St. John's Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings And Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

Risk Summary

There are no adequate and well-controlled studies with omeprazole 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. Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person).

Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg esomeprazole or 40 mg omeprazole (based on body surface area for a 60 kg person). 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 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data].

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H₂-receptor antagonists or other controls.

A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995 to 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 to 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% with 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

Omeprazole

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis 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 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis 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 3.4 to 34 times an oral human doses of 40 mg on a body surface area basis), administered prior to mating through the lactation period.

Esomeprazole

The data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole.

No effects on embryo-fetal development were observed in reproduction studies 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) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis.

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with 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 esomeprazole or 40 mg omeprazole 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 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole 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 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole 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 equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole 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 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis).

Effects on maternal bone were observed in pregnant and lactating rats in the 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 esomeprazole or 40 mg omeprazole 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 equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole 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.

A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

The safety and effectiveness of omeprazole have been established in pediatric patients 1 to 16 years for the treatment of symptomatic GERD, treatment of EE due to acidmediated GERD, and maintenance of healing of EE due to acid-mediated GERD. Use of omeprazole in this age group is supported by adequate and well-controlled studies in adults and uncontrolled safety, efficacy and pharmacokinetic studies performed in pediatric and adolescent patients [see Clinical Pharmacology (12.3), Clinical Studies (14.8)].

The safety and effectiveness of omeprazole have been established in pediatric patients 1 month to less than 1 year of age for the treatment of EE due to acid-mediated GERD and is supported by adequate and well-controlled studies in adults and safety, pharmacokinetic, and pharmacodynamic studies performed in pediatric patients [see Clinical Pharmacology (12.3)].

In the pediatric population, adverse reactions of the respiratory system were frequently reported in the entire (1 month to 16 year) age group. Otitis media was frequently reported in the 1 month to <1 year age group, fever was frequently reported in the 1 to <2 year age group, and accidental injuries were frequently reported in the 2 to 16 year age group [see Adverse Reactions (6.1)].

The safety and effectiveness of omeprazole have not been established in:

patients less than 1 year of age for:
- Treatment of symptomatic GERD
- Maintenance of healing of EE due to acid-mediated GERD
pediatric patients for:
- Treatment of active duodenal ulcer
- H. pylori eradication to reduce the risk of duodenal ulcer recurrence
- Treatment of active benign gastric ulcer
- Pathological hypersecretory conditions
patients less than 1 month of age for any indication.

Juvenile Animal Data

Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazole based on body surface area in a juvenile rat toxicity study. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole.

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Adverse Reactions

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:

Hypersensitivity reactions [see Contraindications (4)] .
Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2)] .
Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.3)] .
Bone Fracture [see Warnings and Precautions (5.4)] .
Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.5)].
Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7)] .
Hypomagnesemia [see Warnings and Precautions (5.8)] .

Drug Interactions

Advise patients to report to their healthcare provider if they start treatment with clopidogrel, St. John's Wort or rifampin; or, if they take high-dose methotrexate [see Warnings and Precautions (5.6, 5.9, 5.11)].

Administration

Take omeprazole delayed-release capsules before meals.
Antacids may be used concomitantly with omeprazole delayed-release capsules.
Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose.

Omeprazole Delayed-Release Capsules

Swallow Omeprazole delayed-release capsules whole; do not chew.
For patients unable to swallow an intact capsule, Omeprazole delayed-release capsules can be opened and administered in applesauce, as described in the Medication Guide.

Medication Guide available at www.zydususa.com/medguides or call 1-877-993-8779.

*CLOtest® is a registered trademark of Kimberly Clark.

MEDICATION GUIDE

Omeprazole ( oh mep' ra zole) Delayed-Release Capsules, USP

Read this Medication Guide before you start taking omeprazole delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about omeprazole delayed-release capsules?

You should take omeprazole delayed-release capsules exactly as prescribed, at the lowest dose possible and for the shortest time needed.

Omeprazole delayed-release capsules may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Omeprazole delayed-release capsules can cause serious side effects, including:

A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including omeprazole delayed-release capsules, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with omeprazole delayed-release capsules. Call your doctor if you have a decrease in the amount that you urinate or if you have blood in your urine.
Diarrhea . Omeprazole delayed-release capsules may increase your risk of getting severe diarrhea. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.
Bone fractures . People who take multiple daily doses of PPI medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist, or spine. You should take omeprazole delayed-release capsules exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take omeprazole delayed-release capsules.
Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body's immune cells attack other cells or organs in the body). Some people who take proton PPI medicines, including omeprazole delayed-release capsules, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun.

Omeprazole delayed-release capsules can have other serious side effects. See "What are the possible side effects of omeprazole delayed-release capsules?"

What are omeprazole delayed-release capsules?

Omeprazole delayed-release capsules are a prescription medicine called a proton pump inhibitor (PPI). Omeprazole delayed-release capsules reduce the amount of acid in your stomach.

Omeprazole delayed-release capsules are used in adults:

for up to 8 weeks for the healing of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
with certain antibiotics for 10 to 14 days to treat an infection caused by bacteria called H. pylori . If needed, your doctor may decide to prescribe another 14 to 18 days of omeprazole delayed-release capsules by itself after the antibiotics. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back.
for up to 8 weeks for healing stomach ulcers.
for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD). GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.
for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE). If needed, your doctor may decide to prescribe another 4 weeks of omeprazole delayed-release capsules.
to maintain healing of the esophagus. It is not known if omeprazole delayed-release capsules are safe and effective when used for longer than 12 months (1 year) for this purpose.
for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison Syndrome.

For children 1 to 16 years of age, omeprazole delayed-release capsules are used:

for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD).

for up to 8 weeks to treat gastroesophageal reflux disease (GERD) with acid-related damage to the lining of the esophagus [called erosive esophagitis (or EE) due to acidmediated GERD].
to maintain healing of the esophagus. It is not known if omeprazole delayed-release capsules are safe and effective when used longer than 12 months (1 year) for this purpose.

For children 1 month to less than 12 months (1 year) of age, omeprazole delayed-release capsules is used:

for up to 6 weeks to treat gastroesophageal reflux disease (GERD) with acid-related damage to the lining of the esophagus [called erosive esophagitis (or EE) due to acidmediated GERD]. It is not known if omeprazole delayed-release capsules is safe and effective for other uses in children 1 month to less than 12 months (1 year) of age, or in children less than 1 month of age.

Who should not take omeprazole delayed-release capsules?

Do not take omeprazole delayed-release capsules if you:

are allergic to omeprazole or any of the ingredients in omeprazole delayed-release capsules. See the end of this Medication Guide for a complete list of ingredients in omeprazole delayed-release capsules.
are allergic to any other proton pump inhibitor (PPI) medicine.
are taking a medicine that contains rilpivirine (EDURANT, COMPLERA) used to treat HIV-1 (Human Immunodeficiency Virus).

What should I tell my doctor before taking omeprazole delayed-release capsules?

Before taking omeprazole delayed-release capsules, tell your doctor about all of your medical conditions, including if you:

have been told that you have low magnesium levels, low calcium levels and low potassium levels in your blood
have liver problems
have any other medical conditions
are pregnant or plan to become pregnant. It is not known if omeprazole delayed-release capsules will harm your unborn baby.
are breastfeeding or plan to breastfeed. Omeprazole passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take omeprazole delayed-release capsules.
Tell your doctor about all of the medicines you take including prescription and over-the- counter medicines, vitamins and herbal supplements. Omeprazole delayed-release capsules may affect how other medicines work, and other medicines may affect how omeprazole delayed-release capsules work. Especially tell your doctor if you take an antibiotic that contains clarithromycin or amoxicillin, or if you take clopidogrel (Plavix), methotrexate (Otrxup, Rasuvo, Trexall), St. John's Wort (Hypericum perforatum), or rifampin (Rimactane, Rifater, Rifamate).

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take omeprazole delayed-release capsules?

Take omeprazole delayed-release capsules exactly as prescribed by your doctor.
Do not change your dose or stop omeprazole delayed-release capsules without talking to your doctor.
Omeprazole delayed-release capsules are usually taken 1 time each day. Your doctor will tell you the time of day to take omeprazole delayed-release capsules, based on your medical condition.
Take omeprazole delayed-release capsules before a meal.
Antacids may be taken with omeprazole delayed-release capsules.

Omeprazole Delayed-Release Capsules

Swallow omeprazole delayed-release capsules whole. Do not chew or crush omeprazole delayed-release capsules .
If you have trouble swallowing a whole capsule, you can open the capsule and take the contents in applesauce. See the "Instructions for Use" at the end of this Medication Guide for instructions on how to take Omeprazole Delayed-Release Capsules with applesauce.

If you miss a dose of omeprazole delayed-release capsules, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time to make up for the missed dose.

If you take too much omeprazole delayed-release capsules, call your doctor or your poison control center at 1-800-222-1222 right away or go to the nearest emergency room.

What are the possible side effects of omeprazole delayed-release capsules? Omeprazole delayed-release capsules can cause serious side effects, including:

See "What is the most important information I should know about omeprazole delayed-release capsules?"
Vitamin B-12 deficiency. Omeprazole delayed-release capsules reduces the amount of acid in your stomach. Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor about the possibility of vitamin B-12 deficiency if you have been on Omeprazole delayed-release capsules for a long time (more than 3 years).
Low magnesium levels in your body. Low magnesium can happen in some people who take a PPI medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium. This problem can be serious.
Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growths called fundic gland polyps, especially after taking PPI medicines for more than 1 year.
Severe skin reactions. Omeprazole delayed-release capsules can cause rare but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening:
Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet).
You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes.

Stop taking omeprazole delayed-release capsules and call your doctor right away. These symptoms may be the first sign of a severe skin reaction.

Tell your doctor right away if you develop any of these symptoms:

seizures
dizziness
abnormal or fast heart beat
jitteriness
jerking movements or shaking (tremors)
muscle weakness
spasms of the hands and feet
cramps or muscle aches
spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking omeprazole delayed-release capsules or during treatment if you will be taking omeprazole delayed-release capsules for a long period of time.

The most common side effects with omeprazole delayed-release capsules in adults and children include:

headache
stomach pain
nausea
diarrhea
vomiting
gas

In addition to the side effects listed above, the most common side effects in children 1 to 16 years of age include:

respiratory system events
fever

Other side effects:

Serious allergic reactions. Tell your doctor if you get any of the following symptoms with omeprazole delayed-release capsules:

rash
face swelling
throat tightness
difficulty breathing

Your doctor may stop omeprazole delayed-release capsules if these symptoms happen.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects with omeprazole delayed-release capsules. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.

How should I store omeprazole delayed-release capsules?

Store Omeprazole Delayed-Release Capsules at room temperature between 59°F to 86°F (15°C to 30°C).
Keep the container of Omeprazole Delayed-Release Capsules closed tightly.
Keep the container of Omeprazole Delayed-Release Capsules dry and away from light.

Keep omeprazole delayed-release capsules and all medicines out of the reach of children.

General information about the safe and effective use of omeprazole delayed-release capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use omeprazole delayed-release capsules for a condition for which it was not prescribed. Do not give omeprazole delayed-release capsules to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about omeprazole delayed-release capsules. For more information, ask your doctor. You can ask your doctor or pharmacist for information that is written for healthcare professionals.

Please address medical inquiries to MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

What are the ingredients in omeprazole delayed-release capsules?

Active ingredient in omeprazole delayed-release capsules: Omeprazole, USP

Inactive ingredients in omeprazole delayed-release capsules: Acetone, di-sodium hydrogen phosphate dihydrate, FD&C blue 1, gelatin, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, polyethylene glycol, sodium lauryl sulphate, sugar spheres, talc, titanium dioxide and triethyl citrate. Additionally each 10 mg and 40 mg capsule shell contains FD&C red 3 and FD&C green 3; each 20 mg capsule shell contains iron oxide red and iron oxide yellow. The capsule is printed with black pharmaceutical ink which contains following ingredients: black iron oxide, potassium hydroxide, propylene glycol and shellac.

*Brands mentioned are the trademarks of their respective owners.

Medication Guide available at www.zydususa.com/medguides or call 1-877-993-8779.

This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug Administration.

What it looks like

Photos of the product and/or packaging supplied by the manufacturer.

Package codes (NDC)

50090-7019-0

Full prescribing information (for healthcare professionals)

SPL UNCLASSIFIED SECTION

Omeprazole Delayed-release Capsules USP, 10 mg are white to off-white free flowing pellets filled in size '3' hard gelatin capsules with amethyst purple- colored cap printed with "ZA-09"in black ink & white body printed with "10 mg" in black ink.

Omeprazole Delayed-release Capsules USP, 20 mg are white to off-white free flowing pellets filled in size '2' hard gelatin capsules with tan-colored cap printed with "ZA-10"in black ink & white body printed with "20 mg" in black ink.

Omeprazole Delayed-release Capsules USP, 40 mg are off-white to pale brown free flowing pellets filled in size'1' hard gelatin capsules with Amethyst purple colored cap printed with "ZA-11" in black ink & white body printed with "40 mg" in black ink.

SPL UNCLASSIFIED SECTION

Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity reactions including anaphylaxis to the formulation [see Warnings and Precautions (5.2)] or any substituted benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria, [see Warnings and Precautions (5.2), Adverse Reactions (6)].
Proton pump inhibitors (PPIs), including omeprazole, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)] .
For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with omeprazole, refer to the CONTRAINDICATIONS section of their package inserts.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, 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.

12.2 Pharmacodynamics

Antisecretory Activity

After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H⁺/K⁺ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days.

Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in healthy subjects and patients are shown below. The "max" value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while "min" values are those 24 hours after the last dose of omeprazole.

Table 5 Range of Mean Values from Multiple Studies of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing

1. Single Studies
Parameter	Omeprazole 20 mg	Omeprazole 40 mg
Max	Min	Max	Min
% Decrease in Basal Acid Output	78¹	58 to 80	94¹	80 to 93
% Decrease in Peak Acid Output	79¹	50 to 59	88¹	62 to 68
% Decrease in 24-hr. Intragastric Acidity		80 to 97		92 to 94

Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24 hour intragastric acidity in some patients.

Serum Gastrin Effects

In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H₂-receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.1)].

Enterochromaffin-like (ECL) Cell Effects

Human gastric biopsy specimens have been obtained from more than 3000 patients (both children and adults) 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. However, 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.

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 intravenous dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans.

However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased.

As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment.

The course of Barrett's esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett's mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett's mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett's mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter.

12.3 Pharmacokinetics

Omeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The systemic exposure increases in a more than dose proportional manner after multiple oral doses of omeprazole. Compared to the first dose, the systemic exposure (C_max and AUC_0-24h) at steady state following once a day dosing increased by 61% and 62%, respectively, compared to after the first dose for the 20 mg dose of omeprazole delayed-release capsules and increased by 118% and 175%, respectively, for the 40 mg dose of omeprazole delayed-release capsules.

Absorption

Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma concentrations of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min.

Based on a relative bioavailability study, the AUC and C_max of Omeprazole for delayed-release oral suspension were 87% and 88% of those for Omeprazole delayed-release capsules, respectively.

The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules.

The systemic exposure (C_max and AUC) are similar when a 40 mg omeprazole delayed-release capsule is administered with and without applesauce. However, administration of a 20 mg omeprazole delayed-release capsule with applesauce, results in a mean 25% reduction in C_max without a significant change in AUC compared to administration without applesauce. The clinical relevance of this finding is unknown.

Distribution

Protein binding is approximately 95%.

Elimination

Metabolism

Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. The major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone.

Excretion

Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were 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.

Combination Therapy with 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 (C_max, AUC_0-24, and T_1/2 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 concentrations of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean C_max was 10% greater, the mean C_min was 27% greater, and the mean AUC_0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean C_max was 45% greater, the mean C_min was 57% greater, and the mean AUC_0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Table 6 Clarithromycin Tissue Concentrations 2 hours after Dose¹

1. Mean ± SD (mcg/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)

Specific Populations

Age: Geriatric Population

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 volunteers, versus 58% in young volunteers 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 volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers.

Age: Pediatric Population

2 to 16 Years of Age

The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age:

Table 7 Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared with Adults

1. Data from single and repeated dose studies. Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules.
2. Data from a single and repeated dose study. Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules.
3. Plasma concentration adjusted to an oral dose of 1 mg/kg.
Single or Repeated Oral Dosing/Parameter	Children¹ ≤ 20 kg 2 to 5 years 10 mg	Children¹ > 20 kg 6 to 16 years 20 mg	Adults² (mean 76 kg) 23 to 29 years (n=12)
Single Dosing
C_max ³(ng/mL)	288 (n=10)	495 (n=49)	668
AUC³(ng h/mL)	511 (n=7)	1140 (n=32)	1220
Repeated Dosing
C_max ³(ng/mL)	539 (n=4)	851 (n=32)	1458
AUC³(ng h/mL)	1179 (n=2)	2276 (n=23)	3352

Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to 16 years of age or adults; AUCs of the latter two groups did not differ [ see Dosage and Administration (2) ].

1 to 11 Months of Age

A population pharmacokinetics model was used to determine appropriate doses of omeprazole in pediatric patients 1 month to less than 1 year of age for treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD. The model was based on data from 64 children 0.5 month to 16 year of age. Only limited data were available in children below the age of 1 year. Pediatric doses were simulated in the age group of 1 to 11 month, to achieve comparable omeprazole exposures with adults following treatment with 20 mg once daily [see Dosage and Administration (2.2)].

Race/Ethnicity

[See Clinical Pharmacology (12.5)].

Renal Impairment

In patients with chronic renal impairment (creatinine clearance between 10 and 62 mL/min/1.73 m²), the disposition of omeprazole 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. This increase in bioavailability is not considered to be clinically meaningful.

Hepatic Impairment

In patients with chronic hepatic disease classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in healthy subjects of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in healthy subjects [see Dosage and Administration (2.1), Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Omeprazole on Other Drugs

Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility.

Antiretrovirals

For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole [see Drug Interactions (7)].

Rilpivirine: Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, C_max by 40%, and C_min by 33% for rilpivirine.

Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C_max by 37% and 89% and C_min by 39% and 75% respectively for nelfinavir and M8.

Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C_max by 96%, and C_min by 95%.

Saquinavir: 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.

AUC was increased by 82%, C_max by 75%, and C_min by 106%. The mechanism behind this interaction is not fully elucidated. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole.

Clopidogrel

In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together.

Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period.

In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions (5.6), Drug Interactions (7)].

Mycophenolate Mofetil

Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA [see Drug Interactions (7)].

Cilostazol

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_max and AUC of cilostazol by 18% and 26% respectively. The C_maxand AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and the above mentioned active metabolite [see Drug Interactions (7)].

Diazepam

Concomitant administration of omeprazole 20 mg once daily and diazepam 0.1 mg/kg given intravenously resulted in 27% decrease in clearance and 36% increase in diazepam half-life [see Drug Interactions (7)].

Digoxin

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions (7)].

Effect of Other Drugs on Omeprazole

Voriconazole

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24 of omeprazole significantly increased: 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 [see Drug Interactions (7)].

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 and 140.8 mg/kg/day (about 0.4 to 34 times a human dose of 40 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times a human dose of 40 mg/day, based on body surface area) for one year, and 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 0.1 to 3.9 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2 year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78 week mouse carcinogenicity 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 in rats (about 34 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24 month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Warnings And Precautions (5)]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H₂-receptor antagonists.

14 CLINICAL STUDIES

SPL UNCLASSIFIED SECTION

Manufactured by:

Zydus Lifesciences Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington,NJ 08534

Rev.: 04/23

SPL UNCLASSIFIED SECTION

Manufactured by:

Zydus Lifesciences Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 09/22

INSTRUCTIONS FOR USE

Omeprazole (oh mep' ra zole) Delayed-Release Capsules, USP

Omeprazole delayed-release capsules

Taking omeprazole delayed-release capsules with applesauce:

Place 1 tablespoon of applesauce into a clean container.
Carefully open the capsule and sprinkle the pellets onto the applesauce. Mix the pellets with the applesauce.
Swallow the applesauce and pellet mixture right away. Do not chew or crush the pellets. Do not store the applesauce and pellet mixture for later use.

SPL UNCLASSIFIED SECTION

Manufactured by:

Zydus Lifesciences Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 09/22

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Important Safety Information

What this medicine is forThe uses this medicine is approved for.

How to take itDosage and administration instructions.

Available doses and forms

Do not use if…Contraindications.

Drug interactionsTables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with Omeprazole delayed-release capsules and instructions for preventing or managi…

Important warnings and precautions

Possible side effectsThe following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2)] Clostridium difficile -Associated Diarrhea [see Warnings and…

Use during pregnancyRisk Summary There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse preg…

Use while breastfeedingRisk Summary Limited data suggest omeprazole may be present in human milk. There are no clinical data on the effects of omeprazole on the breastfed infant or on milk production. The developmental and health benefits of b…

Use in childrenThe safety and effectiveness of omeprazole have been established in pediatric patients 1 to 16 years for the treatment of symptomatic GERD, treatment of EE due to acidmediated GERD, and maintenance of healing of EE due t…

Use in older adultsOmeprazole 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.…

Use in specific groups

If you take too much (overdose)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 vi…

Patient informationAdvise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Adverse Reactions Advise patients to report to their healthcare provider if they experience any signs or symptoms…

Medication GuideMEDICATION GUIDE Omeprazole ( oh mep' ra zole) Delayed-Release Capsules, USP Read this Medication Guide before you start taking omeprazole delayed-release capsules and each time you get a refill. There may be new informa…

What's in this medicineThe active ingredient in omeprazole delayed-release capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid s…

Package label

How it's suppliedProduct: 50090-7019 NDC: 50090-7019-0 90 CAPSULE, DELAYED RELEASE in a BOTTLE

What it looks like

Package codes (NDC)

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION

INSTRUCTIONS FOR USE

SPL UNCLASSIFIED SECTION

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