Heartburn Control Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .............................................................................................. 2

TABLE OF CONTENTS ................................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................ 4

1 INDICATIONS ..................................................................................................................... 4

1.1 Pediatrics ....................................................................................................................... 4

1.2 Geriatrics ....................................................................................................................... 4

2 CONTRAINDICATIONS ........................................................................................................ 4

4 DOSAGE AND ADMINISTRATION ........................................................................................ 4

4.1 Dosing Considerations ................................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment .............................................................. 4

4.4 Administration .............................................................................................................. 5

4.5 Missed Dose .................................................................................................................. 5

5 OVERDOSAGE .................................................................................................................... 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ........................................ 5

7 WARNINGS AND PRECAUTIONS ......................................................................................... 6

7.1 Special Populations ....................................................................................................... 9

7.1.1 Pregnant Women .......................................................................................................... 9

7.1.2 Breast-feeding ............................................................................................................... 9

7.1.3 Pediatrics ....................................................................................................................... 9

7.1.4 Geriatrics ....................................................................................................................... 9

8 ADVERSE REACTIONS ....................................................................................................... 10

8.1 Adverse Reaction Overview ........................................................................................ 10

8.2 Clinical Trial Adverse Reactions ................................................................................... 10

8.5 Post-Market Adverse Reactions .................................................................................. 13

9 DRUG INTERACTIONS ....................................................................................................... 13

9.1 Serious Drug Interactions ............................................................................................ 13

9.2 Drug Interactions Overview ........................................................................................ 13

9.3 Drug-Behavioural Interactions .................................................................................... 14

9.4 Drug-Drug Interactions ................................................................................................ 14

9.5 Drug-Food Interactions ............................................................................................... 20

9.6 Drug-Herb Interactions ............................................................................................... 20

9.7 Drug-Laboratory Test Interactions .............................................................................. 20

10 CLINICAL PHARMACOLOGY .............................................................................................. 20

10.1 Mechanism of Action .................................................................................................. 20

10.2 Pharmacodynamics ..................................................................................................... 20

10.3 Pharmacokinetics ........................................................................................................ 22

11 STORAGE, STABILITY AND DISPOSAL ................................................................................ 25

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................. 25

PART II: SCIENTIFIC INFORMATION ......................................................................................... 26

13 PHARMACEUTICAL INFORMATION ................................................................................... 26

14 CLINICAL TRIALS ............................................................................................................... 26

14.1 Clinical Trials by Indication .......................................................................................... 26

14.2 Comparative Bioavailability Studies ............................................................................ 27

15 MICROBIOLOGY ............................................................................................................... 30

16 NON-CLINICAL TOXICOLOGY ............................................................................................ 30

17 SUPPORTING PRODUCT MONOGRAPHS ........................................................................... 34

PATIENT MEDICATION INFORMATION .................................................................................... 35

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

HEARTBURN CONTROL (Omeprazole delayed-release capsules) capsules are indicated for:

• the treatment of frequent heartburn. Frequent heartburn is heartburn that occurs 2 or more days a week.

HEARTBURN CONTROL capsules are not indicated for infrequent heartburn (i.e. one episode of heartburn a week or less) or immediate relief of heartburn.

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. See 7.1.3 Pediatrics.

1.2 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. See 7.1.4 Geriatrics.

2 CONTRAINDICATIONS

Omeprazole delayed-release capsules are contraindicated in:

• Patients who have hypersensitivity to this drug, substituted benzimidazoles or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Co-administration with rilpivirine due to significant decrease in rilpivirine exposure and loss of therapeutic effect. See 9.4 Drug-Drug Interactions, Rilpivirine.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Patients should use the lowest dose and shortest duration of Proton Pump Inhibitor (PPI) therapy appropriate to the condition being treated.
• Concomitant use of omeprazole and clopidogrel should be avoided. See 7 WARNINGS AND PRECAUTIONS, General, Clopidogrel and 9.4 Drug-Drug Interactions, Clopidogrel.

4.2 Recommended Dose and Dosage Adjustment

• Adults 18 years and older: The recommended dose of HEARTBURN CONTROL (omeprazole) for adults 18 years and older is 1 capsule given once daily for 14 days for the treatment of frequent heartburn (i.e., for heartburn that occurs more than 2 days a week). The maximum dose is 1 capsule in a 24-hour period. Symptom relief should be rapid. If symptom control is
• A 14-day course of therapy may be repeated every 4 months.
• Patients with Renal Impairment: No dose adjustment is required. See 7 WARNINGS AND PRECAUTIONS, Renal.
• Patients with Hepatic Impairment: No dose adjustment is required. The maximum daily dose (20 mg) should not be exceeded. See 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic.
• Geriatrics (>65 years of age): No dose adjustment is required. The maximum daily dose (20 mg) should not be exceeded. See 7.1.4 Geriatrics.

4.4 Administration

The capsules should be swallowed whole with sufficient water. The capsules must not be chewed or crushed.

4.5 Missed Dose

If you miss a dose of HEARTBURN CONTROL and remember within 12 hours, take it as soon as possible. Then go back to your regular schedule. However, if more than 12 hours have passed when you remember, do not take the missed capsule. Do not double the dose. Just take your next dose on time.

5 OVERDOSAGE

Rare reports have been received of overdosage with omeprazole. Single oral doses of up to 400 mg of omeprazole capsules have not resulted in any severe symptoms, and no specific treatment has been needed. One case report described that a single oral dose (560 mg) of omeprazole was associated with moderate increase of white blood cells, generalised malaise, nausea, vomiting, apathy, confusion, drowsiness, moderate headache, flatulence and abdominal pain. As in all cases where overdosing is suspected, treatment should be supportive and symptomatic. Any unabsorbed material should be removed from the gastrointestinal tract, and the patient should be carefully monitored.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

HEARTBURN CONTROL (omeprazole) 20 mg capsules are two-piece hard gelatin capsules with an opaque pink body and an opaque reddish-brown cap, imprinted “APO 020”.

Available in 14 capsules blister packages.

7 WARNINGS AND PRECAUTIONS

General

In the presence of any alarming symptoms (e.g., nausea, significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, melena or anemia) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment may alleviate symptoms and delay diagnosis.

Drug Interactions with Antiretroviral Drugs: Proton Pump Inhibitors (PPIs) have been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. A change in gastric pH may change the absorption of the antiretroviral drug. Other possible mechanisms are via CYP 2C19.

Rilpivirine: Co-administration is contraindicated due to significant decrease in rilpivirine exposure and loss of therapeutic effect. See 2 CONTRAINDICATIONS.

Atazanavir and Nelfinavir: Concomitant administration with atazanavir and nelfinavir is not recommended due to decreased atazanavir and nelfinavir exposure. See 9.4 Drug-Drug Interactions, Antiretroviral drugs.

If the combination of omeprazole with atazanavir is judged unavoidable, close clinical monitoring is recommended in combination with the use of 400 mg atazanavir/100 mg ritonavir dose; the dose of HEARTBURN CONTROL should not exceed the maximum daily dose (20 mg) (see REYATAZ Product Monograph).

Saquinavir: If omeprazole is co-administered with saquinavir/ritonavir, caution and monitoring for potential saquinavir toxicities, including gastrointestinal symptoms, increased triglycerides, deep vein thrombosis and QT prolongation are recommended. Dose reduction of saquinavir should be considered from the safety perspective for individual patients (see INVIRASE Product Monograph).

Clopidogrel: Results from studies in healthy subjects have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole (80 mg once daily, i.e. four times the

recommended dose) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 46% and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 16%. Based on these data, concomitant use of omeprazole and clopidogrel should be avoided. See 9.4 Drug-Drug Interactions, Clopidogrel.

Concomitant use of Proton Pump Inhibitors (PPIs) 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. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate. See 9.4 Drug-Drug Interactions, Methotrexate.

Patients should be advised to consult their healthcare professional if:

• Their heartburn continues or worsens.
• They need to take omeprazole for more than 14 days or require more than 1 course of treatment within a 4-month period.
• They experience heartburn with light-headedness, sweating or dizziness.
• They have chest pain or shoulder pain with shortness of breath, sweating, pain spreading to arms, neck or shoulders, or light-headedness.
• They have frequent chest pain.
• They have frequent wheezing, particularly with heartburn.
• They have stomach pain.

Carcinogenesis and Mutagenesis

Short-term treatment and long-term treatment with omeprazole capsules in a limited number of patients for up to 6 years have not resulted in any significant pathological changes in gastric oxyntic endocrine cells.

Endocrine and Metabolism

Hypomagnesaemia, Hypokalemia and Hypocalcemia: The chronic use of PPIs may lead to hypomagnesaemia. Moreover, hypokalemia and hypocalcemia have been reported in the literature as accompanying electrolyte disorders.

Cyanocobalamin (Vitamin B₁₂) Deficiency: The prolonged use of PPIs, may impair the absorption of protein-bound Vitamin B₁₂ and may contribute to the development of cyanocobalamin (Vitamin B₁₂) deficiency.

Gastrointestinal

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Decreased gastric acidity due to any means, including any PPIs, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with PPIs may lead to a slightly increased risk of gastrointestinal infections such as Salmonella, Campylobacter and possibly Clostridium difficile.

Long-term use of omeprazole is associated with an increased risk of fundic gland polyps especially beyond one year. See 8.5 Post-Market Adverse Reactions. Most fundic gland polyps are asymptomatic. Use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Hepatic/Biliary/Pancreatic

Hepatic Impairment: Information on the bioavailability of omeprazole 20 mg capsules in patients with hepatic insufficiency is not currently available. However, based on data obtained from studies with i.v. administration of omeprazole and oral administration of omeprazole capsules, patients with impaired liver function showed a 75% increase in bioavailability, reduced total plasma clearance (to 67 mL/min) and a 4-fold prolongation of the elimination half-life (to 2.8 hours). A dose of 20 mg omeprazole capsules given once daily to these patients for 4 weeks was well tolerated, with no accumulation of omeprazole or its metabolites. The daily dose in patients with severe liver disease should, as a rule, not exceed 20 mg. See 4.2 Recommended Dose and Dosage Adjustment.

Immune

Subacute cutaneous lupus erythematosus: Subacute cutaneous lupus erythematosus (SCLE) has been reported with the use of PPIs. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping HEARTBURN CONTROL. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs. See 8.5 Post-Market Adverse Reactions.

Musculoskeletal

Bone Fracture: Several published observational studies suggest that 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 4 DOSAGE AND ADMINISTRATION and 8 ADVERSE REACTIONS.

Renal

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking omeprazole and may occur at any point during omeprazole therapy. Acute tubulointerstitial nephritis can progress to renal failure. Omeprazole should be discontinued in case of suspected TIN, and appropriate treatment should be promptly initiated. See 8.5 Post-Market Adverse Reactions.

Renal Impairment: Information on the bioavailability of omeprazole 20 mg capsules in patients with renal insufficiency is not currently available. However, based on data obtained from studies with i.v. administration of omeprazole and oral administration of omeprazole capsules, the disposition of intact omeprazole is unchanged in patients with impaired renal function, and no dose adjustment is needed in these patients. See 4.2 Recommended Dose and Dosage Adjustment.

Reproductive Health: Female and Male Potential

• Fertility

  In animal studies, fertility and reproductive performance were not affected. See 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity.

• Teratogenic Risk

  There was no evidence of teratogenicity following administration of omeprazole to pregnant rats and rabbits during the period of organogenesis. See 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicity.

7.1 Special Populations

7.1.1 Pregnant Women

The safety of omeprazole in pregnancy has not been established. HEARTBURN CONTROL capsules should not be administered to pregnant women unless the expected benefits outweigh the potential risks.

7.1.2 Breast-feeding

Omeprazole is secreted in human milk. HEARTBURN CONTROL capsules should not be given to breastfeeding mothers unless its use is considered essential.

7.1.3 Pediatrics

Pediatrics (<18 years of age): The safety and effectiveness of omeprazole delayed-release capsules in children have not yet been established. Omeprazole capsules should not be used in children under 18 years of age.

7.1.4 Geriatrics

Geriatrics (>65 years of age): In data obtained from studies with intravenous (i.v.) administration of omeprazole and oral administration of omeprazole capsules, elderly subjects showed increased bioavailability (36%), reduced total plasma clearance (to 250 mL/min) and prolonged (50%) elimination of half-life (to 1.0 hour). The dose in elderly patients should not exceed the maximum daily dose (20 mg). See 4.2 Recommended Dose and Dosage Adjustment.

Geriatrics (>71 years of age): Benefits of use of PPIs should be weighed against the increased risk of fractures as patients in this category may already be at high risk for osteoporosis-related fractures. If the use of PPIs is required, they should be managed carefully according to established treatment guidelines. See 4.2 Recommended Dose and Dosage Adjustment and 8.5 Post-Market Adverse Reactions.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Omeprazole is well tolerated. Most adverse reactions have been mild and transient, and have shown no consistent relationship with treatment.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Adverse events have been recorded during 6 placebo-controlled clinical investigations of OTC omeprazole involving 6,286 subjects who took omeprazole (3,146 on omeprazole 20 mg and 3,139 on omeprazole 10 mg) and 3,120 subjects who took placebo. The most commonly reported adverse events in the omeprazole 20 mg group were headache (3%), diarrhea (2%) and infection (2%). These incidences were not significantly greater than those observed in subjects treated with placebo.

Table 2 - Most Common Adverse Events in OTC Subjects in Placebo-Controlled Studies

The percentage of discontinuations due to adverse events was also similar for omeprazole-treated subjects (0.5%) compared to placebo-treated subjects (0.6%), and were primarily due to nausea, headache, vomiting, diarrhea and/or abdominal pain.

The incidence of serious adverse events (SAEs) was low: 0.2% for omeprazole 20 mg subjects and 0.1% for placebo subjects. No SAE reported by subjects receiving omeprazole 20 mg was considered to be possibly or probably related to study medication.

The following is a list of adverse events reported in clinical trials or reported from routine post-marketing surveillance of short term and chronic use of omeprazole. Events are classified within body system categories. The following definitions of frequencies are used: common: ≥1/100; uncommon: ≥1/1,000 and <1/100, rare: ≥1/10,000 and <1/1,000 and very rare: <1/10,000.

Blood and lymphatic system disorders

Rare: leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.

Very rare: aplastic anemia and bone marrow suppression.

Cardiac disorders

Very rare: serious arrhythmia (increased QT interval, torsade de pointes, ventricular fibrillation, ventricular tachycardia).

Ear and labyrinth disorders

Very rare: tinnitus, vertigo, hearing loss and ear pain.

Eye disorders

Rare: blurred vision

Very rare: eye pain, papilledema, optic atrophy.

Gastrointestinal disorders

Common: diarrhea, constipation, abdominal pain, nausea/vomiting and flatulence.

Rare: dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis and pancreatitis (some fatal).

General disorders and administration site conditions

Uncommon: malaise.

Rare: increased sweating, peripheral edema.

Hepatobiliary disorders

Uncommon: increased liver enzyme levels.

Rare: encephalopathy in patients with pre-existing severe liver disease, hepatocellular necrosis requiring liver transplantation, hepatitis with or without jaundice and hepatic failure.

Immune system disorders

Uncommon: hypersensitive reactions including urticaria.

Rare: hypersensitive reactions including angioedema, fever and anaphylactic shock

Metabolism and nutrition disorders

Rare: hyponatremia

Very rare: hypomagnesemia (severe hypomagnesemia may result in hypocalcemia, and hypomagnesemia may also result in hypokalemia).

Musculoskeletal and connective tissue disorders

Rare: arthralgia, muscular weakness and myalgia.

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very rare: gastric polyps, gastric cancer and gastric carcinoids.

Nervous system disorders

Common: headache.

Uncommon: dizziness, paresthesia, somnolence and vertigo.

Rare: taste disturbances.

Psychiatric disorders

Uncommon: insomnia.

Rare: reversible mental confusion, agitation, aggression, depression and hallucination occurring predominantly in severely ill patients.

Renal and urinary disorders

Rare: interstitial nephritis (decreased volume of urine, fever, rash, joint stiffness), glycosuria, haematuria and pyuria.

Reproductive system and breast disorders

Rare: gynaecomastia.

Very rare: impotence, decreased fertility.

Respiratory, thoracic and mediastinal disorders

Rare: bronchospasm.

Skin and subcutaneous tissue disorders

Uncommon: rash, dermatitis and/or pruritus, and urticaria.

Rare: photosensitivity, erythema multiforme, Stevens-Johnsons syndrome, toxic epidermal necrolysis (TEN) and alopecia.

8.5 Post-Market Adverse Reactions

Gastrointestinal disorders: Withdrawal of long-term PPI therapy can lead to aggravation of acid related symptoms and may result in rebound acid hypersecretion.

There have been post-marketing reports of microscopic colitis and fundic gland polyps (PGPs). See 7 WARNINGS AND PRECAUTIONS, Gastrointestinal.

Musculoskeletal and connective tissue disorders: Osteoporosis and osteoporosis-related fractures have been reported with multiple daily doses and long-term PPI therapy.

Renal and urinary disorders: There have been post-marketing reports of tubulointerstitial nephritis (with possible progression to renal failure).

Skin and subcutaneous tissue disorders: There have been post-marketing reports of acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), subacute cutaneous lupus erythematosus (SCLE). See 7 WARNINGS AND PRECAUTIONS, Immune.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

The gastric acid suppression during treatment with omeprazole and other PPIs might decrease or increase the absorption of drugs with gastric pH dependent absorption. Thus, it can be predicted that the absorption of drugs such as ketoconazole, itraconazole and erlotinib can decrease during omeprazole treatment, as it does during treatment with other acid secretion inhibitors or antacids.

Omeprazole is metabolized by the cytochrome P-450 system (CYP), mainly in the liver. The pharmacokinetics of the following drugs, which are also metabolized through the cytochrome P-450 system, have been evaluated during concomitant use of omeprazole capsules in humans: aminopyrine, antipyrine, clopidogrel, diazepam, phenytoin, warfarin (or other vitamin K antagonists), cilostazol^*, theophylline, voriconazole, digoxin, propranolol, metoprolol, lidocaine, quinidine, ethanol, piroxicam, diclofenac and naproxen.

Omeprazole inhibits CYP 2C19, the major omeprazole metabolizing enzyme, and is partially metabolized by CYP 3A4. Drugs known to inhibit CYP 2C19 or CYP 3A4 or both (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by decreasing the rate of omeprazole’s metabolism. Drugs known to induce CYP 2C19 or CYP 3A4 or both (such as rifampin and St John’s Wort) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism.

As omeprazole is metabolized through CYP 2C19, it can alter the metabolism and prolong elimination of diazepam, warfarin (R-warfarin), phenytoin, and cilostazol^*.

^*not marketed in Canada

There is a modest increase in the absorption of digoxin when omeprazole is co-administered in daily doses of 20 mg or 40 mg. This increase may be clinically relevant in patients who have renal impairment or are especially susceptible to digoxin toxicity.

Results from a range of interaction studies with omeprazole vs. other drugs indicate that omeprazole, 20 to 40 mg given repeatedly, has no influence on other clinically relevant isoforms of CYP, as shown by the lack of metabolic interaction with substrates for CYP 1A2 (caffeine, phenacetin, theophylline), CYP 2C9 (S-warfarin), CYP 2D6 (metoprolol, propranolol), CYP 2E1 (ethanol), and CYP 3A (cyclosporin, estradiol, lidocaine, quinidine).

9.3 Drug-Behavioural Interactions

Ethanol: There was no significant effect on the pharmacokinetics of ethanol after treatment with omeprazole 20 mg.

Driving and Operating Machinery: HEARTBURN CONTROL is not likely to affect the ability to drive or use machines.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3 - Established or Potential Drug-Drug Interactions

^* not marketed in Canada

9.5 Drug-Food Interactions

No interaction with food after repeated dosing of omeprazole capsules has been found.

9.6 Drug-Herb Interactions

Drugs known to induce CYP 2C19 or CYP 3A4 or both, such as St John’s Wort (Hypericum performatum) may lead to decreased omeprazole serum levels by increasing omeprazole’s rate of metabolism.

9.7 Drug-Laboratory Test Interactions

During treatment with antisecretory drugs, serum gastrin increases in response to the decreased acid secretion. Also chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that PPI treatment should be stopped 5 to 14 days before CgA measurement.

Measurements should be repeated if levels have not normalized by this time.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Omeprazole inhibits the gastric enzyme H⁺/K⁺-ATPase (the proton pump) which catalyzes the exchange of H+ and K+. Omeprazole is effective in the inhibition of both basal acid secretion and stimulated acid secretion. The inhibition is dose-dependent. Daily oral doses of omeprazole 20 mg and higher showed a consistent and effective acid control.

10.2 Pharmacodynamics

Pharmacotherapeutic group: Proton pump inhibitors, ATC-code: A02BC01

In both normal volunteers and hypersecretors, omeprazole inhibited basal nocturnal and daytime acid secretion as well as meal-, histamine-, and pentagastrin-stimulated secretion (omeprazole capsule data).

Table 4 - Percentage Inhibition of Mean Acid Output After Single Oral Doses of Omeprazole.

Repeated oral dosing with 20 mg of omeprazole once daily provided rapid inhibition of gastric acid secretion, with the maximum effect achieved within the first four days of treatment. Gastric emptying was unaffected by omeprazole.

Information from clinical trials in patients with duodenal ulcers in remission indicate that omeprazole demonstrate the inhibition of stimulated acid secretion and a mean reduction of 24- hour intragastric pH of approximately 80% was achieved during repeated dosing of 20 mg daily. The mean decrease in peak acid output after pentagastrin stimulation was about 70% 24 hours after repeated dosing with omeprazole 20 mg. Omeprazole caused a transient decrease in stimulated pepsin output which resolved within four hours of dosing. Omeprazole had no effect on intrinsic factor secretion.

Other Pharmacodynamic Effects

The effect of omeprazole on various organ systems has been investigated (data taken from clinical studies using omeprazole capsules). No clinically significant effects attributable to the drug could be found for the following parameters:

• Endocrine: plasma levels of insulin, C- peptide, glucagon, parathyroid hormone, thyroid hormones or sex hormones, basal levels of cortisol;
• Cardiovascular: blood pressure, heart rate, electrocardiogram;
• Renal: renal handling of acid and electrolytes;
• Hepatic: liver enzymes.

However, in some patients receiving omeprazole, elevated concentrations of alkaline phosphatase, S-AST and S-ALT have been reported. See 8 ADVERSE REACTIONS.

An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in both children and adults during long term treatment with omeprazole. The findings are considered to be of no clinical significance.

No clinically significant central nervous system effects have been recorded.

No clinically significant effects on other organ systems have been noted.

Omeprazole has no effect on acetylcholine or H₂-receptors.

Investigation in man has demonstrated an initial moderate increase in gastrin levels during treatment with omeprazole, but no further increase occurred during long-term (up to three years) treatment. No significant changes have been found in the endocrine cells of the oxyntic gastric mucosa during short- or long-term treatment with omeprazole in man, to date. Chronic treatment of patients with Zollinger-Ellison Syndrome with mean daily doses of omeprazole of 60 mg/day for up to five years has not influenced the pre-treatment hypergastrinemia, and no changes in the endocrine cells of the gastric mucosa have been found on repeat biopsies.

10.3 Pharmacokinetics

Table 5 - Summary of Omeprazole Pharmacokinetic Parameters in Healthy Male Volunteers

^§ Expressed as the median

Absorption

Omeprazole is absorbed rapidly. After an initial oral dose of omeprazole, approximately 35% of the drug is absorbed from the gastrointestinal tract. Following one week of therapy, the percentage absorbed is 43. Neither food nor antacids have any effect on the bioavailability of the capsule. After oral administration, peak plasma levels occur within about 4 hours. The terminal plasma half-life is approximately 40 minutes; the total plasma clearance is 0.6 L/min. Although the antisecretory effect of omeprazole is directly proportional to the AUC; it is not dependent on the plasma concentration at any given time.

The 20 mg tablet and the 20 mg capsule are not bioequivalent in terms of plasma omeprazole AUC (geometric ratio and 90% confidence interval: 1.18, 1.06 to 1.30), C_max (1.41, 1.24 to 1.60) and T. Omeprazole 20 mg tablets demonstrate, after repeated dosing, increased plasma omeprazole AUC (18%) and maximum concentration (41%) in comparison to omeprazole 20 mg given as capsules.

Ninety-five to 100% of duodenal ulcer and 80% of gastric ulcer patients are H. pylori-positive and should be treated with eradication therapy. Eradication of H. pylori is associated with long-term remission of peptic ulcer disease. Long-term treatment of these patients with antisecretory agents is generally not recommended. Long-term treatment with omeprazole is effective in the prevention of relapse of duodenal or gastric ulcer, as demonstrated in clinical studies in patients with unknown H. pylori status, and may be used for the minority of patients who are H. pylori- negative.

The bioavailability of amoxicillin was studied during concomitant administration with omeprazole in fasting healthy adult subjects. When a single dose of amoxicillin, 750 mg, was administered to subjects who had received repeated doses of omeprazole 40 mg twice daily for three weeks, no significant change in the bioavailability (AUC, C_max) of amoxicillin was observed.

Clarithromycin 500 mg three times daily and omeprazole 40 mg capsules once daily were studied following concomitant administration in fasting healthy adult subjects. When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC_0-24 were observed. For all subjects combined, the mean omeprazole AUC_0-24 was 89% greater and the harmonic mean for omeprazole t½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C_max, C_min and AUC_0-8 of clarithromycin were increased by 10%, 27% and 15%, respectively, over values achieved when clarithromycin was administered with placebo.

The omeprazole capsule (as a multiple unit formulation) is usually emptied gradually from the stomach into the intestine. In contrast to the capsule, the tablet (as a single unit formulation) will enter the intestine and dissolve as one unit. Consequently, the absorption and first pass metabolism of the tablet take place during a very limited period. This may be one of the reasons for the difference observed in the pharmacokinetic variables of the two formulations.

Distribution

Omeprazole is 95% bound to plasma proteins.

Metabolism

Omeprazole undergoes first pass metabolism and is completely metabolized by the cytochrome P- 450 system, mainly in the liver, through CYP 2C19 and CYP 3A4. The major part of its metabolism is dependent upon the polymorphically expressed, specific isoform CYP 2C19 (S-mephenytoin hydroxylase). The remaining part is dependant on another specific isoform, CYP 3A4, responsible for the formation of omeprazole sulphone. As a consequence of high affinity of omeprazole to CYP 2C19, there is a potential for competitive inhibition and metabolic drug-drug interactions with other substrates for CYP 2C19. However, due to low affinity to CYP 3A4, omeprazole has no potential to inhibit the metabolism of other CYP 3A4 substrates.

The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP 2C19 enzyme, extensive metabolisers.

Total plasma clearance is about 30 to 40 L/h after a single dose. The plasma elimination half-life of omeprazole is usually shorter than one hour both after single and repeated oral once-daily dosing. The AUC of omeprazole increases with repeated administration. This increase is dose-dependant and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP 2C19 enzyme by omeprazole and/or its metabolites (eg. the sulphone). Omeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.

Poor metabolisers: Approximately 3% of the Caucasian population and 15 to 20% of Asian populations lack a functional CYP 2C19 enzyme and are called poor metabolisers. In such individuals the metabolism of omeprazole is expected to be catalysed by CYP 3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5 to 10 times higher in poor metabolisers than in subjects having a functional CYP 2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were also higher, by 3 to 5 times. However, these findings have no implication on dosing of omeprazole.

Elimination

Following i.v. administration and oral administration (capsules) of omeprazole, 80% of the dose is recovered as urinary metabolites. The remaining 20% is excreted in the feces. Less than 0.1% of the dose administered is excreted in urine as unchanged drug.

Six urinary metabolites have been detected. The two main metabolites have been identified as hydroxyomeprazole and the corresponding carboxylic acid. Three metabolites have been identified in plasma, the sulphide and sulphone derivatives and hydroxyomeprazole. It is unlikely that these metabolites contribute to inhibition of acid secretion.

Special Populations and Conditions

• Geriatrics: Elderly subjects showed a 36% increase in bioavailability, reduced total plasma clearance (to 250 mL/min) and reduced urinary excretion of metabolites. Elimination half-life (to 1.0 hour) was also prolonged by 50%. The mean urinary excretion of metabolites was 68% of the dose. These changes are consistent with reduction in pre-systemic and systemic elimination, typical in the elderly. The daily dose shouldnot exceed the maximum daily dose (20 mg) in this patient group. See 7.1.4 Geriatrics and 4.2 Recommended Dose and Dosage Adjustment).
• Genetic Polymorphism & Ethnic Origin: CYP 450 2C19 is a polymorphic enzyme. This heterogeneity is more pronounced in the Asian population where the proportion of slow metabolizers is higher than in Caucasians. In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately 4-fold was noted in Asian subjects compared to Caucasians. The half-life of omeprazole in slow metabolizers is about 2.5 hours as compared to approximately 1 hour for rapid metabolizers. It is recommended that Asian populations be closely followed-up, particularly when doses are higher than 20 mg and/or there is concomitant hepatic disease.
• Hepatic Insufficiency: Patients with impaired liver function showed a 75% increase in bioavailability, reduced total plasma clearance (to 67 mL/min), and a 4-fold prolongation of the elimination half-life (to 2.8 hours). Twenty mg given once daily to these patients for 4 weeks was well tolerated. Dosage for patients with liver cirrhosis and other liver dysfunction shouldnot exceed the maximum daily dose (20 mg) . See 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic.
• Renal Insufficiency: The pharmacokinetics of omeprazole in patients with impaired renal function was virtually the same as in healthy subjects. See 7 WARNINGS AND PRECAUTIONS, Renal.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15˚C - 30˚C. Protect from moisture.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Heartburn

The prevention of frequent heartburn by omeprazole magnesium has been examined in two pivotal randomized, double-blind, placebo-controlled trials conducted in 2,086 subjects with heartburn 2 or more days per week. With consecutive daily dosing for 14 days, omeprazole- treated subjects had a significantly greater percentage of heartburn free days than did placebo- treated patients (64.4% vs. 39.4%; p<0.001, Study 1 and 67.8% vs. 37.9%; p<0.001, Study 2). Omeprazole magnesium-treated subjects had a greater percentage of nights with no nocturnal heartburn symptoms (84.7% vs. 74.5%; p≤0.05, Study 1 and 86.1% vs. 75.4%; p≤0.05, Study 2). Consecutive daily dosing with omeprazole magnesium also resulted in a greater percentage of days with no more than mild heartburn vs. placebo. For all 14-day outcomes, omeprazole magnesium provided significantly greater protection against heartburn than placebo in both studies.

14.2 Comparative Bioavailability Studies

A randomized, single dose, blinded, 2-way crossover comparative bioavailability study, conducted under fasting conditions, was performed on healthy male volunteers. The results obtained from 18 volunteers who completed the study are summarized in the following table. The rate and extent of absorption of omeprazole was measured and compared following a single oral dose (2 x 20 mg capsules) of omeprazole 20 mg capsule (Apotex Inc.) and LOSEC^® (omeprazole) 20 mg capsule (Astra Pharma).

Summary Table of the Comparative Bioavailability Data

A randomized, single dose, blinded, 2-way crossover comparative bioavailability study, conducted under fed conditions, was performed on healthy male volunteers. The results obtained from 19 volunteers who completed the study are summarized in the following table. The rate and extent of absorption of omeprazole was measured and compared following a single oral dose (2 x 20 mg capsules) of omeprazole 20 mg capsule (Apotex Inc.) and LOSEC^® (omeprazole) 20 mg capsule (Astra Pharma).

Summary Table of the Comparative Bioavailability Data

A randomized, single dose, 2-way crossover comparative bioavailability study, conducted under fasting conditions, was performed on healthy male volunteers. The results obtained from 36 volunteers who completed the study are summarized in the following table. The rate and extent of absorption of omeprazole was measured and compared following a single oral dose (2 x 20 mg capsules) of omeprazole 20 mg capsule (Apotex Inc.) and Prilosec^® (omeprazole) 20 mg capsule (Astra Merck).

Summary Table of the Comparative Bioavailability Data

A randomized, single dose, 2-way crossover comparative bioavailability study, conducted under fed conditions, was performed on healthy male volunteers. The results obtained from 34 volunteers who completed the study are summarized in the following table. The rate and extent of absorption of omeprazole was measured and compared following a single oral dose (2 x 20 mg capsules) of omeprazole 20 mg capsule (Apotex Inc.) and Prilosec^® (omeprazole) 20 mg capsule (Astra Merck).

Summary Table of the Comparative Bioavailability Data

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity

Table 6 - Single-Dose Toxicity Studies of Omeprazole

The highest oral dose (4,000 mg/kg) of non-micronized omeprazole did not cause death in any of the species tested. With micronized omeprazole, suspended in Methocel^®, the acute oral LD₅₀ was approximately 1,500 mg/kg in mice; in male rats, higher than the maximum dose (5,000 mg/kg); and in female rats, approximately 3000 mg/kg. As much as 80% of the compound may not have been absorbed due to acid degradation of these single doses in the stomach. Death occurred within 2 days of ingestion and was preceded by reduced motor activity, reduced respiration frequency but increased respiration depth, reduced body temperature, and twitching, tremor or convulsions. The highest oral dose given to dogs (660 mg/kg) caused vomiting within 40 to 100 minutes of ingestion. The acute i.v. LD₅₀ was 83 mg/kg in male mice, and in female mice >100 mg/kg. The corresponding figure in rats was >40 mg/kg. Death occurred within a few minutes of injection, preceded by cyanosis and convulsions.

The oral LD₅₀ of omeprazole in male and female rats and mice was greater than 4,000 mg/kg. In dogs, the only sign of acute toxicity was vomiting which occurred at doses of approximately 600 mg/kg.

Long-Term General Toxicity

The general, long-term toxicity of omeprazole was studied in mice, rats, and dogs after oral and intravenous administration. Mice received oral doses of 14 to 140 mg/kg for up to 18 months, rats 14 to 400 mg/kg for up to 24 months and dogs 1 to 140 mg/kg for up to 12 months. Intravenous omeprazole was given to rats in doses of 2 to 16 mg/kg for up to one month and dogs 1 to 9 mg/kg for up to one month.

In the dog, a slight to moderate atrophy of the chief cells and rugal hypertrophy were observed. These changes were reversible after treatment cessation.

Following chronic intravenous administration of omeprazole to rats (~1.7 to 15.5 mg/kg/day) for one month and to dogs (~0.7 to 8.6 mg/kg/day) for one month, no treatment-related changes were observed.

In the rat, decreased plasma concentrations of triiodothyronine were observed in the two highest groups; TSH increased in the high-dose males. Lower doses had no significant effect. General hypertrophy of the oxyntic mucosa was found; the size of some chief cells was decreased and some granularity was observed. Both the hypertrophy and chief cell changes were reversible.

Carcinogenicity

An 18-month oral study was conducted in mice at doses of 14, 44, and 140 mg/kg/day. No evidence of carcinogenic potential was seen. A 24-month oral study was conducted in rats at doses of 14, 44, and 140 mg/kg/day. No increase in carcinomas was observed in any organ. However, there were dose- and time-dependent increases of tumour-like proliferations in the stomach.

Histology showed a continuum from diffuse ECL-cell hyperplasia in the basal region of the gastric glands to less frequent micronoduli and occasional tumour-like proliferations, some extending into the submucosa. The proliferations were classified as gastric carcinoids. The proliferation of ECL- cells and development of carcinoids were more frequent in female rats. No metastases were identified in any of the animals. Carcinoids have not been observed after long-term administration of omeprazole to mice and dogs.

Gastric ECL-Cell Carcinoids

Extensive investigations have been carried out to explain the ECL-cell hyperplasia and the gastric carcinoid findings in rats. Gastrin produced by the G-cells in the antrum plays an important role in the feedback control of gastric acid secretion.

In one series of experiments, the antrum of rats was surgically excluded from the rest of the stomach. The removal of acid from the antrum in this way led to pronounced hypergastrinemia and, secondary to this, gastric ECL-cell proliferation. Antrectomy, which removes the source of gastrin, led to a decrease in gastric ECL-cell density. These experiments indicated that gastrin has a direct trophic effect on gastric ECL-cells. In another series of experiments, high doses of omeprazole and a histamine H2-receptor blocker caused hypergastrinemia and increased ECL-cell density. In antrectomized rats given a high dose of omeprazole, plasma gastrin levels remained normal, and consequently there was no increase in ECL-cell density. It has therefore been concluded that (i) inhibition of gastric acid secretion by large doses of omeprazole or a histamine H2-receptor blocker, evokes a natural feedback response leading to hypergastrinemia, (ii) long- standing hypergastrinemia leads to gastric ECL-cell proliferation, and (iii) there is no direct trophic effect of omeprazole on gastric ECL-cells. Similar observations have been made after administration of histamine H₂-receptor blockers and also in partially fundectomized rats.

An additional long-term (24 months) toxicity study in female rats (1.8 to 14 mg/kg/day) confirmed that the ECL-cell carcinoids were extreme end-life tumours and that there was a linear correlation between carcinoid incidence and dose of omeprazole (1.8 to 140 mg/kg/day). In rats given omeprazole 14 mg/kg/day for 12 months, no carcinoids were found and the ECL-cell hyperplasia recovered to normal during the next 12 months of no treatment.

No carcinoids have been found in mice, and in dogs following administration of 28 mg/kg/day for 7 years.

Genotoxicity

Omeprazole was tested in vivo (mouse micronucleus test, chromosome aberration in mice) and in vitro (Ames test, mouse lymphoma forward mutation assay) and showed no evidence of a mutagenic effect.

Pharmacodynamics

Omeprazole differs from existing inhibitors of gastric acid secretion such as histamine H2- receptor antagonists and anticholinergic agents in its ability to directly inhibit the gastric H⁺/K⁺- ATPase. This enzyme has been identified as the proton pump of the parietal cell.

Omeprazole had a long duration of action in all species studied. Repeated daily doses resulted in a progressive increase in the antisecretory effect during the first 3 to 5 days of administration. In dogs, a dose of 0.5 micromol/kg (given as enteric coated granules) inhibited histamine-stimulated gastric acid secretion by about 20% when measured 24 hours after the first dose, and by 60 to 65% when measured 24 hours after dosing at steady state. Once steady state conditions were reached (after 3to 5 days), acid inhibition remained unchanged, as established in dogs treated for periods of up to one year.

Acid secretion recovers after discontinuation of long-term treatment at the same rate as after a single dose of omeprazole, in parallel with the recovery of H⁺/K⁺-ATPase activity in the oxyntic mucosa. Whether this recovery reflects de novo synthesis of the H⁺/K⁺-ATPase molecules or the dissociation of the inhibitor from the enzyme has not yet been established.

Due to the potency and long duration of action of omeprazole, repeated administrations of high doses in the rat resulted in a marked decrease of acid secretion and a secondary hypergastrinemia and hyperplasia of G-cells. In rats, administration of omeprazole 14 to 140 mg/kg/day resulted in plasma gastrin levels of 1,000 to 3,000 pg/mL as compared to 150 to 200 pg/mL in controls. In dogs, high doses of omeprazole (28 mg/kg/day) produced marked hypergastrinemia (1,000 to 2,000 pg/mL after food intake), as compared to 100 to 300 pg/mL in controls. However, no hyperplasia of G-cells was evident in this species.

Secondary Pharmacological Effects

Mean arterial blood pressure and heart rate in the anesthetized dog were not affected by omeprazole under various challenges. Circulatory and respiratory functions in the dog were not affected by omeprazole, either at rest or during exercise. Omeprazole had no anticholinergic and no antihistamine (H₂-receptor) activity. In the rat, no effect on basal locomotor activity or on exploratory activity was recorded, suggesting that omeprazole is devoid of sedative or neuroleptic effects.

Other Interactions

Omeprazole interacts with cytochrome P-450 in the rat liver. Omeprazole prolonged hexobarbital sleeping time by 12%.

Pharmacokinetics

Absorption and Distribution

Omeprazole is degraded rapidly in acidic gastric juice (rat and dog studies). Absorption is rapid. Peak plasma levels were found within 20 minutes and 1 hour after intra-duodenal and oral administration, respectively, in the dog. The drug has a low oral bioavailability, 5% in unstarved rats and 15 to 20% in starved male and female rats, if the drug is not protected by an enteric coating. The intra-duodenal bioavailability is approximately 70% and the oral bioavailability is approximately 15% in the dog. After absorption, omeprazole is rapidly distributed to extravascular sites and about 95% is bound to plasma proteins. The distribution of ¹⁴C-labelled omeprazole in the mouse was investigated by autoradiography. Radioactivity was initially found in the blood and most organs. Sixteen hours after administration, the drug was confined predominantly to the stomach wall. At 48 hours, the radioactivity was eliminated.

Penetration of omeprazole and/or its metabolites across the blood-brain and placental barriers was low.

Metabolism and Excretion

Omeprazole was extensively metabolized in all species studied. In rats and dogs approximately 20 to 30% of the dose was excreted as urinary metabolites and the remainder by biliary excretion as metabolites in the feces. Elimination was virtually complete within 72 hours. Identifiable metabolites constituted about 50% (rat) and 70% (dog) of the total metabolite excretion in 24 hours, and about 12% of the given dose in both species.

A study in lactating rats showed that omeprazole is excreted in breast milk. The concentration in the milk at 3 to 5 hours post dose was 100 to 200 times lower than the plasma concentration. It is not known if omeprazole is excreted in human milk.

Reproductive and Developmental Toxicity

In studies with male and female rats given oral doses of up to 138 mg/kg/day (approximately 500 times the recommended human dose), fertility and reproductive performance were not affected.

In rabbits, increased embryo-lethality and fetal resorption were observed at maternotoxic doses of 69 and 138 mg/kg/day (250 and 500 times the human dose). No maternal or fetal toxicity was observed in pregnant rats treated at doses ranging from 13.8 to 138 mg/kg/day (50 to 500 times the human dose). In rats, a slight decrease in litter size at birth and slightly impaired postnatal viability and growth were observed in offspring resulting from parents treated with high doses of 138 mg/kg/day (500 times the human dose) of omeprazole. Similar effects were not seen at lower doses.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. OLEX^TM (Omeprazole (as omeprazole magnesium) delayed release tablets, 20 mg), submission control 161377, Product Monograph, PENDOPHARM, Division of Pharmascience Inc., (MAR 27, 2013)
2. 2. APO-OMEPRAZOLE (Omeprazole Delayed-Release Capsules, 20 mg), submission control 273446, Product Monograph Apotex Inc., (AUG 31, 2023)