5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis

Acute Tubulointerstitial Nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non- specific symptoms of decrease renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever rash or arthralgia). Discontinue omeprazole delayed-release capsules and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.3 Clostridium difficile-Associated Diarrhea

Published observational studies suggest that PPI therapy like omeprazole may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with omeprazole, refer to Warnings and Precautions sections of the corresponding prescribing information.

5.4 Bone Fracture

Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis- related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2.1), Adverse Reactions (6.3)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue omeprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving omeprazole, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Interaction with Clopidogrel

Avoid concomitant use of omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole, consider alternative anti-platelet therapy [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

5.8 Cyanocobalamin (Vitamin B-12) Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with omeprazole.

5.9 Hypomagnesemia and Mineral Metabolism

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].

Consider monitoring magnesium and calcium levels prior to initiation of omeprazole delayed-release capsules and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.10 Interaction with St. John's Wort or Rifampin

Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can substantially decrease omeprazole concentrations [see Drug Interactions (7)]. Avoid concomitant use of omeprazole with St. John’s Wort or rifampin.

5.11 Interactions with Diagnostic Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop omeprazole 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 [see Drug Interactions (7)].

5.12 Interaction with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)].

5.13 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

17 PATIENT COUNSELING INFORMATION

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 (5.6)]
• Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.8)].
• Hypomagnesemia [see Warnings and Precautions (5.9)].

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 (5.7, 5.10, 5.12)].

Administration

• Take omeprazole before meals.
• Antacids may be used concomitantly with omeprazole.
• 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.

Dispense with Medication Guide available at www1.apotex.com/products/us

---

APOTEX INC.
OMEPRAZOLE DELAYED-RELEASE CAPSULES, USP
10 mg, 20 mg and 40 mg

Manufactured by	Manufactured for
Apotex Inc.	Apotex Corp.
Toronto, Ontario	Weston, Florida
Canada M9L 1T9	USA 33326

Revision: 30

INSTRUCTIONS FOR USE

Omeprazole delayed-release capsules
(oh mep’ ra zole)

Taking Omeprazole Delayed-Release Capsules with applesauce:

1. Place 1 tablespoon of applesauce into a clean container.

2. Carefully open the capsule and sprinkle the pellets onto the applesauce. Mix the pellets with the applesauce.

3. 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.

APOTEX INC.
OMEPRAZOLE DELAYED-RELEASE CAPSULES, USP
10 mg, 20 mg and 40 mg

Manufactured by	Manufactured for
Apotex Inc.	Apotex Corp.
Toronto, Ontario	Weston, Florida
Canada M9L 1T9	USA 33326

Revised: May 2023

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Adult Dosage Regimen by Indication

Table 1 shows the recommended dosage of omeprazole in adult patients by indication.

Table 1: Recommended Dosage Regimen of Omeprazole in Adults by Indication

Indication	Dosage of Omeprazole	Treatment Duration
Treatment of Active Duodenal Ulcer	20 mg once daily	4 weeks1
Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence	Triple Therapy Omeprazole 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg Take all three drugs twice daily	10 days In patients with an ulcer present at the time of initiation of therapy, continue omeprazole 20 mg once daily for an additional 18 days for ulcer healing and symptom relief.
	Dual Therapy Omeprazole 40 mg once daily Clarithromycin 500 mg three times daily	14 days In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.
Active Benign Gastric Ulcer	40 mg once daily	4 to 8 weeks
Treatment of Symptomatic GERD	20 mg once daily	Up to 4 weeks
Treatment of EE due to Acid- Mediated GERD	20 mg once daily	4 to 8 weeks2
Maintenance of Healing of EE due to Acid-Mediated GERD	20 mg once daily3	Controlled studies do not extend beyond 12 months.
Pathological Hypersecretory Conditions	Starting dose is 60 mg once daily; adjust to patient needs Daily dosages of greater than 80 mg should be administered in divided doses. Dosages up to 120 mg three times daily have been administered.	As long as clinically indicated. Some patients with Zollinger- Ellison syndrome have been treated continuously for more than 5 years.

1. Most patients heal within 4 weeks; some patients may require an additional 4 weeks of therapy to achieve healing
2. The efficacy of omeprazole used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8-week courses of omeprazole may be considered.
3. Dosage reduction to 10 mg once daily is recommended for patients with hepatic impairment (Child-Pugh Class A, B or C) and Asian patients when used for the maintenance of healing of EE [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3, 12.5)].

2.2 Recommended Pediatric Dosage Regimen by Indication

Table 2 shows the recommended dosage of omeprazole in pediatric patients by indication.

Table 2: Recommended Dosage Regimen of Omeprazole in Pediatric Patients by Indication

Indication	Omeprazole Dosage Regimen and Duration
Patient Age	Weight-Based Dose (mg)	Regimen and Duration
Treatment of Symptomatic GERD	1 to 16 years	5 to less than 10 kg: 5 mg	Once daily for up to 4 weeks
10 to less than 20 kg: 10 mg
20 kg and greater: 20 mg
Treatment of EE due to Acid-Mediated GERD	1 to 16 years	5 to less than 10 kg: 5 mg	Once daily for 4 to 8 weeks1
10 to less than 20 kg: 10 mg
20 kg and greater: 20 mg
1 month to less than 1 year	3 to less than 5 kg: 2.5 mg	Once daily up to 6 weeks
5 to less than 10 kg: 5 mg
10 kg and greater: 10 mg
Maintenance of Healing of EE due to Acid-Mediated GERD	1 to 16 years	5 to less than 10 kg: 5 mg	Once daily. Controlled studies do not extend beyond 12 months
10 to less than 20 kg: 10 mg
20 kg and greater: 20 mg

1. The efficacy of omeprazole used for longer than 8 weeks in patients with EE has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of EE or GERD symptoms (e.g., heartburn), additional 4 to 8-week courses of omeprazole may be considered.

2.3 Administration Instructions

• Take omeprazole before meals.
• Antacids may be used concomitantly with omeprazole.
• 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 as follows:

1. Place one tablespoon of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing.
2. Open the capsule.
3. Carefully empty all of the pellets inside the capsule on the applesauce.
4. Mix the pellets with the applesauce.
5. Swallow applesauce and pellets immediately with a glass of cool water to ensure complete swallowing of the pellets. Do not chew or crush the pellets. Do not save the applesauce and pellets for future use.