Riva-Esomeprazole DR Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

Riva-ESOMEPRAZOLE DR (esomeprazole) is indicated for treatment of conditions where a reduction in gastric acid secretion is required such as:

• reflux esophagitis
• maintenance treatment of patients with reflux esophagitis
• nonerosive reflux disease (NERD) (i.e. heartburn and regurgitation)
• healing of NSAID*-associated gastric ulcers
• reduction of risk of NSAID-associated gastric ulcers
• treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome
• Helicobacter pylori (H. pylori) eradication

Riva-ESOMEPRAZOLE DR, in combination with clarithromycin and amoxicillin, is indicated for the treatment of patients with duodenal ulcer disease associated with Helicobacter pylori infection to eradicate the H. pylori and heal ulcers. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

*Note: Superiority of esomeprazole magnesium over ranitidine 150 mg BID with the use of non-selective NSAIDs was demonstrated. Superiority was not established with the use of COX-2 selective NSAIDs alone due to the small number of patients analyzed in this subgroup (See Table 10 in the Clinical Trial section).

Pediatrics (12-17 years of age)

Riva-ESOMEPRAZOLE DR (esomeprazole) is indicated for treatment of conditions where a reduction in gastric acid secretion is required such as:

• reflux esophagitis
• nonerosive reflux disease (NERD) (i.e. heartburn and regurgitation)

Riva-ESOMEPRAZOLE DR IS NOT RECOMMENDED FOR USE IN CHILDREN UNDER 12 YEARS OF AGE

CONTRAINDICATIONS

• Hypersensitivity to esomeprazole, substituted benzimidazoles or any of the components of this medication (see Dosage Forms, Composition and Packaging).
• When used for eradication of Helicobacter pylori, the contraindications for amoxicillin and clarithromycin as found in the corresponding Product Monographs should be taken into consideration.

WARNINGS AND PRECAUTIONS

General

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

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 proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections such as Salmonella, Campylobacter and possibly Clostridium difficile.

Concomitant administration with atazanavir or nelfinavir is not recommended (see DRUG INTERACTIONS).

Carcinogenesis and Mutagenesis

Long-term toxicity studies of omeprazole, revealed the gastric mucosa as the target organ. The carcinogenic potential of esomeprazole was assessed using omeprazole studies. In the rat carcinogenicity study (24 months), ECL-cell carcinoids were found in some animals treated with 14-140 mg/kg/day for their normal life span. ECL-cell carcinoids were seen in a background of ECL-cell hyperplasia. No ECL-cell carcinoids were identified in the carcinogenicity study in mice or in long-term (up to 7 years) general toxicity studies in dogs.

A vast number of studies have revealed that pronounced and sustained hypergastrinemia is the mechanism behind the development of the gastric ECL-cell carcinoids in the rat. Such ECL carcinoids have been seen in rats after life-long treatment with other inhibitors of acid secretion such as H2-receptor blockers and other proton pump inhibitors. Partial fundectomy in rats results in hypergastrinemia and gastric ECL-cell carcinoids in the remaining part of the fundic mucosa, towards the end of the rats’ life span.

Treatment with esomeprazole for up to 1 year in more than 800 patients has not resulted in any significant pathological changes in the gastric oxyntic endocrine cells. Short- term treatment and long-term treatment with the racemate, omeprazole, capsules in a limited number of patients for up to 11 years have not resulted in any significant pathological changes in gastric oxyntic endocrine cells.

During treatment with all antisecretory drugs serum gastrin increases in response to the decreased acid secretion. The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months (daily doses of either 20 or 40 mg). The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau (approximately 100 pg/mL) within two to three months of therapy and returned to baseline levels (approximately 30-40 pg/mL) within four weeks after discontinuation of therapy.

Special Populations

Pregnant Women: The safety of esomeprazole in pregnancy has not been established. Esomeprazole should not be administered to pregnant women unless the expected benefits outweigh the potential risks.

Nursing Women: It has not been investigated whether or not esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore, esomeprazole should not be given to nursing mothers unless its use is considered essential.

Pediatrics (12-17 years of age): The use of esomeprazole in pediatric patients (12 to 17 years of age) for the short term treatment (up to 8 weeks) of GERD is supported by extrapolation of results already included in the currently approved labelling from a) adequate and well-controlled studies in adults that supported the approval of esomeprazole for adults, and additionally from b) safety and pharmacokinetic studies performed in pediatric patients (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Pediatrics (12-17 years of age), ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions, Pediatrics (12-17 years of age) and CLINICAL TRIALS, In Pediatrics (12-17 years of age)).

No data is currently available in children (1-11 years of age) with hepatic insufficiency (see DOSAGE AND ADMINISTRATION).

The safety and effectiveness of esomeprazole have not yet been established in pediatric patients <1 years of age.

Geriatrics (> 71 years of age): The metabolism of esomeprazole is not significantly changed in elderly subjects. Following repeated oral dosing with 40 mg esomeprazole in healthy elderly subjects (6 males, 8 females; 71 to 80 years of age), AUC and C_max values measured were similar to those previously measured in young GERD patients (ratio of AUC values in elderly vs. GERD subjects: 1.25; ratio of C_max values: 1.18). Therefore, dose adjustment is not required in the elderly.

Gender: The AUC and C_max values were slightly higher (13%) in females than in males at steady state. Dosage adjustment based on gender is not necessary.

Hepatic Insufficiency: The metabolism of esomeprazole magnesium in patients with mild to moderate liver dysfunction (Child Pugh Class A or B), is similar to that in patients with symptoms of GERD with normal liver function. Metabolism of esomeprazole is decreased in patients with severe liver dysfunction (Child Pugh Class C) resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. The plasma elimination half-life in patients with severe liver dysfunction is still very short (3 hours) relative to the dosing interval (24 hours). Esomeprazole and its major metabolites do not show any tendency to accumulate with once-daily dosing. Dose adjustment is not required in patients with mild to moderate liver impairment. A daily dose of 20 mg in patients with severe liver disease should not, as a rule, be exceeded (see DOSAGE AND ADMINISTRATION).

Renal Insufficiency: Since the kidney is responsible for the excretion of metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Esomeprazole is extensively protein-bound and is, therefore, not expected to be readily dialyzable. Dose adjustment is not required in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).

Poor Metabolizers: The CYP 2C19 and CYP 3A4 isozymes are responsible for metabolism of esomeprazole. CYP 2C19, which is involved in the metabolism of all available proton pump inhibitors, exhibits polymorphism. Approximately 3% of Caucasians and 15-20% of Asians lack CYP 2C19 and are termed “poor metabolizers”. At steady state, the ratio of AUC in poor metabolizers to AUC in the rest of the population is approximately 2. Dosage adjustment of esomeprazole based on CYP 2C19 status is not necessary.

Monitoring and Laboratory Tests

The clinical documentation for esomeprazole does not support the need for routine laboratory monitoring of response to therapy. (See WARNINGS and PRECAUTIONS – Carcinogenesis and Mutagenesis for effects of esomeprazole on serum gastrin levels and ADVERSE REACTIONS

• Post-Market Adverse Drug Reactions for effects on liver functioning).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Esomeprazole is well-tolerated. Most adverse reactions have been mild and transient, showing no consistent relationship with treatment.

Adverse reactions have been recorded during controlled clinical investigations in >8500 adult patients exposed to esomeprazole. Additionally >1200 adult subjects/patients were exposed to esomeprazole in Phase I studies. Among reactions which occurred with a frequency of >1% in clinical studies, only headache, diarrhea, flatulence, abdominal pain, nausea, vomiting, dizziness and dry mouth are thought to be associated with the use of esomeprazole.

Adverse reactions have been recorded during a clinical investigation in 109 pediatric patients (1-11 years of age) exposed to esomeprazole. Among reactions which occurred with a frequency of >1% in clinical studies, only diarrhea, headache and somnolence are associated with the use of esomeprazole. No new safety concerns were identified. Adverse reactions have also been recorded during a clinical investigation in 149 pediatric patients (12-17 years of age) exposed to esomeprazole. The treatment related adverse event profile was found to be consistent with that seen in adults.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adults

The following adverse reactions, irrespective of causal relationship, were reported (at a rate of more than 1%) in controlled short-term (up to 8 weeks) clinical trials involving 5668 patients: Table 1 Percentage of Patients Reporting Adverse Reactions, Irrespective of

Causal Relationship, (at a Rate of More than 1%) in Short Term Clinical Trials (Up to 8 weeks) Treated With Esomeprazole.

In clinical trials up to 6 months’ duration, the following adverse reactions were reported.

Table 2 Percentage of Patients Reporting Adverse Reactions, Irrespective of Causal

Relationship, (at a Rate of More than 3%) in Clinical Trials Up to 6 Months’ Duration Treated With Esomeprazole.

*endoscopic assessment

Additionally, the following adverse reactions (irrespective of causality) were each reported at a rate of >1% with esomeprazole in these same long-term studies (n=519): rash, fracture, hernia, dizziness, duodenitis, dyspepsia, epigastric pain, serum gastrin increased, gastroenteritis, GI mucosal discoloration, esophageal disorder, tooth disorder, SGPT (serum glutamic pyruvic transaminase) increased, hypertension, coughing, rhinitis, anemia, benign GI neoplasm, back pain, chest pain, and fatigue.

Clinical experience for up to one year in over 800 patients with doses of esomeprazole of 40 mg have shown a similar adverse reaction pattern to that seen in short-term trials. In addition to the adverse reactions listed above, the following adverse reactions were reported (at a rate of more than 1%), irrespective of causal relationship (mean duration of treatment = 294 days): accident/injury (7.6%), pain (4.3%), urinary tract infection (3.7%), bronchitis (3.6%), arthralgia (2.9%), hypertension (2.6%), allergy (2.1%), insomnia (2.1%), hypercholesterolemia (2.0%),

anxiety (1.7%), gastroesophageal reflux (1.6%), fever (1.5%), ear infection (1.5%), flu-like disorder (1.4%), myalgia (1.2%), arthropathy (1.1%), dyspnea (1.1%), overdose (1.1%).

H. pylori Eradication Combination Therapy

In clinical studies, a total of 446 patients received esomeprazole in combination with amoxicillin and clarithromycin for 7 days. The following adverse reactions were reported (at a rate of more than 1%), irrespective of causal relationship: diarrhea (21.5%), taste perversion (12.6%), headache (3.6%), dry mouth (3.4%), SGPT increased (1.8%), flatulence (1.6%), nausea (1.3%), stomatitis (1.3%), vomiting (1.1%) and pharyngitis (1.1%). However, it should be noted that taste perversion is commonly associated with clarithromycin treatment and diarrhea is commonly associated with antibiotic treatment.

When esomeprazole is used in combination with amoxicillin and clarithromycin, the Product Monographs for those agents must be consulted and followed.

Healing of Gastric Ulcers Associated with NSAID Therapy

The data presented in this section is derived from two short-term gastric ulcer healing studies comprising 836 patients.

Table 3 Percentage of Patients reporting Adverse Reactions that were

Assessed by the Investigator to have a reasonable causal relationship with Treatment (at a Rate of >1%) in Short Term Clinical Trials (up to 8 Weeks), for the healing of gastric ulcers associated with NSAID therapy.

The following adverse reactions occurred (<1% for esomeprazole) in clinical trials for the healing of gastric ulcers associated with NSAID therapy, and were considered causally related by the investigator:

Gastrointestinal: abdominal pain, epigastric pain, gastric retention, gastric ulcer, gastroesophageal reflux, nausea, peptic ulcer aggravated

Liver and Bilary: abnormal hepatic function, increased SGOT, increased SGPT Metabolic & Nutritional: increased phosphatase alkaline

Nervous System: headache

Psychiatric: insomnia

Special Senses: taste perversion

The following adverse events (considered unrelated to esomeprazole by the investigator) were each reported at a frequency of >1% in clinical trials for the healing of gastric ulcers; gastric ulcer aggravated, mucosal discoloration GI, gastrointestinal symptoms NOS, esophageal stricture, esophagitis, vomiting, constipation, duodenitis, rash, anxiety, pharyngitis, respiratory infection, sinusitis, urinary tract infection, accident and/or injury, and back pain.

In addition, the following adverse events of a potentially severe nature (considered unrelated to esomeprazole by the investigator) were reported in these same studies; cardiac failure aggravated, hypertension/hypertension aggravated, syncope, arrhythmia, bradycardia, atrial fibrillation, palpitation/palpitation aggravated.

Risk-reduction of Gastric Ulcers Associated with NSAID Therapy

The data presented in this section is derived from two long-term ulcer risk-reduction studies comprising 1390 patients.

Table 4 Percentage of Patients reporting Adverse Reactions that were

Assessed by the Investigator to have a reasonable causal relationship with Treatment (at a Rate of >1%) in Long Term Clinical Trials (up to 6 months), for the risk-reduction of gastric ulcers associated with NSAID therapy.

The following adverse reactions occurred (<1% for esomeprazole) in clinical trials for the risk- reduction of gastric ulcers associated with NSAID therapy, and were considered causally related by the investigator:

Body as a Whole: asthenia, back pain

Blood System: anemia, leukopenia, thrombocytopenia

Gastrointestinal: constipation, defecation urge, duodenitis, epigastric pain, eructation, gastric retention, gastric ulcer, dry mouth, mucosal discolouration GI, frequent stools, vomiting Liver and Biliary: hepatic enzymes increased NOS, increased SGOT, increased SGPT Metabolic & Nutritional: dehydration, weight decrease, weight increase Neoplasms: GI neoplasm

Nervous System: dizziness, headache, hyperesthesia, vertigo

Psychiatric: anorexia, increased appetite, insomnia, sleep disorder

Resistance Mechanism: herpes simplex

Skin: rash

Special Senses: taste perversion

The following adverse events (considered unrelated to esomeprazole by the investigator) were each reported at a frequency of >1% in clinical trials for the risk-reduction of gastric ulcers; arthralgia, arthrosis, aggravated rheumatoid arthritis, cramps, myalgia, rash, urticaria, dizziness, headache, neuropathy, insomnia, constipation, duodenitis, epigastric pain, gastric mucosal lesion NOS, mucosal discoloration GI, esophageal disorder, esophagitis, vomiting, dry mouth, increased SGOT, increased SGPT, bronchitis, coughing, dyspnoea, pharyngitis, respiratory infection, sinusitis, anemia, thrombocythemia, micturation frequency, urinary tract infection, benign GI neoplasm, accident/or injury, back pain, chest pain, fatigue, peripheral edema, pain, and postoperative complications.

In addition, the following adverse events of a potentially severe nature (considered unrelated to esomeprazole by the investigator) were reported in these same studies; cardiac failure, hypertension/hypertension aggravated, tachycardia, palpitation, atrial fibrillation, extrasystoles, bradycardia, arrhythmia, myocardial fibrosis, coronary artery disorder, syncope, thrombocytopenia, leucopenia, and cholelithiasis.

Zollinger-Ellison Syndrome

In an open label, 12 month clinical study conducted in 21 patients with either Zollinger-Ellison syndrome or idiopathic hypersecretion, single cases of the following adverse events, not previously listed under other indications, were reported with esomeprazole use, irrespective of causality: abdominal rigidity, asthma, Barrett’s esophagus, carcinoid tumour of the stomach, carpal tunnel syndrome, depression, erosive gastritis, gingival abscess, hematuria, hyperparathyroidism, hypoesthesia, hypokalemia, hypomagnesemia, hypothyroidism, mean cell volume decreased, melena, muscle spasms, neoplasm progression, osteoporosis, parathesia, pharyngolaryngeal pain, postoperative pain, proteinuria, pruritus, rhinorrhea.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Skin: dermatitis, pruritus and urticaria

Nervous System: paresthesia

Rare Clinical Trial Adverse Drug Reactions (<0.1%)

Body as a Whole: malaise

Metabolic & Nutritional: hyponatremia

Very Rare Clinical Trial Adverse Drug Reactions (<0.01%)

Body as a Whole: muscular weakness

Hepatic & Biliary: hepatic encephalopathy

Abnormal Hematologic and Clinical Chemistry Findings

See ADVERSE REACTIONS – Post-Market Adverse Drug Reactions, and WARNINGS and PRECAUTIONS – Carcinogenesis and Mutagenesis.

Pediatrics (12-17 years of age)

In children (12 – 17 years) with Gastroesophageal Reflux Disease (GERD)

In a multicentre, randomized, double-blind, parallel-group safety and tolerability study in 149 pediatric patients (12 – 17 years of age; 89 female, 124 Caucasian, 15 Black, 10 Other) with clinically diagnosed GERD), adverse events were recorded after exposure to esomeprazole 20 mg and 40 mg once daily for up to 8 weeks. Patients were not endoscopically characterized as to the presence or absence of erosive esophagitis.

The observed adverse event profile was found to be consistent with that seen in adults, with treatment related events of headache (8.1%), abdominal pain (2.7%), diarrhea (2.0%), and nausea (2.0%) commonly reported. No new safety concerns were identified for this population.

Post-Market Adverse Drug Reactions

From post-marketing experience there have been uncommon reports (<1%) of peripheral edema, insomnia, paresthesia, somnolence, vertigo, increased liver enzymes.

There have been rare reports (<0.1%) of blurred vision, hypersensitivity reactions (e.g. angioedema, anaphylactic reaction/shock), myalgia, leukopenia, thrombocytopenia, depression, alopecia, hepatitis with or without jaundice, hyponatremia, agitation, confusion, taste disturbance, bronchospasm, stomatitis, GI candidiasis, rash, dermatitis, photosensitivity, arthralgia, malaise, and hyperhidrosis.

Very rarely (<0.01%) agranulocytosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancytopenia, aggression, hallucination, hepatic failure, hepatic encephalopathy, interstitial nephritis, muscular weakness, gynecomastia, hypomagnesaemia and microscopic colitis have been reported.

As of 25 June 2007, 48 medically confirmed case reports with 84 adverse events in children between 12 and 17 years of age have been received. Five of the 48 cases were reported within approved label use, while 43 cases constituted off-label use. An overall assessment of the adverse events reported after within-label and off-label use in children ages 12-17 years raised no safety concerns with esomeprazole treatment in this age group.

DRUG INTERACTIONS

Overview

Esomeprazole magnesium is metabolized by the cytochrome P-450 system (CYP), mainly in the liver, through CYP 2C19 and CYP 3A4. There are no clinically significant interactions between esomeprazole and diazepam, phenytoin, quinidine or cisapride*. Drugs known to inhibit CYP 2C19 or CYP 3A4 or both (such as clarythromycin and voriconazole) may lead to increased esomeprazole serum levels by decreasing the rate of esomeprazole’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 esomeprazole serum levels by increasing the esomeprazole metabolism.

With on-demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole, should be considered when esomeprazole is prescribed in this manner (see DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

Diazepam: Concomitant administration of esomeprazole (30 mg once daily for 5 days) resulted in a 45% decrease in the clearance of diazepam in healthy male volunteers. Studies in females have not been conducted. Increased levels of diazepam were seen some 12 hours after dosing and later when the plasma levels of diazepam were below its therapeutic range. Therefore, this interaction is unlikely to be of clinical significance.

Warfarin: Concomitant administration of 40 mg esomeprazole (once daily for 3 weeks) to male and female patients on stable anticoagulation therapy with warfarin, resulted in a 13% increase in trough plasma levels of R-warfarin (the less potent enantiomer) while that of S-warfarin was unchanged. Coagulation times were stable throughout the entire study period. No clinically significant interaction was observed. However, from post marketed use, cases of elevated international normalized ratio (INR) of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarin derivatives (please refer to approved Product Monograph for warfarin or relevant coumarin derivative).

Cilostazol^∗: Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites, 3,4- dihydrocilostazol, by 29% and 69% respectively.

Phenytoin: Concomitant administration of 40 mg esomeprazole (once daily for 2 weeks) to male and female epileptic patients stabilized on phenytoin, resulted in a 13% increase in trough plasma levels of phenytoin. This minor interaction is unlikely to be of clinical relevance as dose reduction was not required in any patient nor was the profile and frequency of adverse events affected.

Results from a range of interaction studies with esomeprazole versus other drugs indicate that

^∗ not marketed in Canada

daily doses of 40 mg esomeprazole, given for 5 to 21 days in male and/or female subjects, has no clinically relevant interactions with CYP 1A2 (caffeine), CYP 2C9 (S-warfarin), and CYP 3A (quinidine, estradiol and cisapride^∗).

Methotrexate: When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. In patients administered high doses of methotrexate, a temporary withdrawal of esomeprazole may need to be considered.

Antiretroviral Drugs: Omeprazole, like other acid-reducing agents, has 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 interaction mechanisms are via CYP 2C19.

Reports indicate that omeprazole has a significant impact on atazanavir exposure, decreasing AUC, C_max and C_min. This interaction is only partially overcome by the addition of ritonavir to the atazanavir treatment regimen. Similarly, decreased serum levels of nelfinavir have also been reported when given together with omeprazole. Concomitant administration of omeprazole with atazanavir and nelfinavir is therefore not recommended. For other antiretroviral drugs, such as saquinavir, increased serum levels have been reported. There are also some antiretroviral drugs where unchanged serum levels have been reported when given with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and antiretroviral drugs such as atazanavir and nelfinavir is not recommended (see WARNINGS AND PRECAUTIONS).

Voriconazole: Concomitant administration of esomeprazole with a combined inhibitor of CYP 2C19 and CYP 3A4 may result in more than double the levels of esomeprazole exposure.

As with all drugs that reduce gastric acidity, changes in plasma levels of other drugs whose absorption is pH dependent (e.g. ketoconazole, itraconazole or erlotinib) must be taken into account when they are co-administered with esomeprazole. The absorption of ketoconazole, itraconazole or erlotinib can decrease during treatment with esomeprazole.

Digoxin: The absorption of digoxin can increase during treatment with esomeprazole and other drugs that reduce gastric acidity. Concomitant treatment with omeprazole (20 mg daily) and digoxin in ten healthy subjects increased the bioavailability of digoxin by an average of 10% (up to 30% in two out of ten subjects).

Drug-Food Interactions

Food intake delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

^∗ not marketed in Canada

Drug-Laboratory Test Interactions

During treatment with antisecretory drugs, chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. To avoid this interference esomeprazole treatment should be temporarily stopped five days before CgA measurements.

Other Interactions

As demonstrated with other PPIs, prolonged use may impair the absorption of protein-bound Vitamin B₁₂ and may contribute to the development of Vitamin B₁₂ deficiency.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The capsules should be swallowed whole with sufficient water. DO NOT open, divide, crush or chew the capsules. Do NOT open the capsules to sprinkle on food or beverages.

Recommended Dose and Dosage Adjustment

Adults

Treatment of conditions where a reduction of gastric acid secretion is required:

Reflux Esophagitis: The recommended dose in patients with reflux esophagitis is 40 mg Riva-ESOMEPRAZOLE DR once daily for 4 to 8 weeks in order to optimize the healing rate and symptom resolution. Healing occurs in the majority of patients within 4 weeks. Sustained freedom from symptoms is achieved rapidly for most patients. An additional 4 weeks of treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.

Maintenance of Healing of Erosive Esophagitis: For the long-term treatment of patients whose reflux esophagitis has been healed with acid suppression therapy, the recommended dose is 20 mg Riva-ESOMEPRAZOLE DR once daily. Controlled studies do not extend beyond 6 months.

Nonerosive reflux disease: In patients with heartburn and/or acid regurgitation, without esophagitis, the recommended dose is 20 mg Riva-ESOMEPRAZOLE DR once daily for 2 to 4 weeks. If symptom control is not achieved after 4 weeks of treatment, further investigation is recommended.

Maintenance Treatment of NERD (On-demand): For the maintenance of symptom relief in patients whose symptoms were initially controlled after daily doses for 2 to 4 weeks, the recommended dose is 20 mg Riva-ESOMEPRAZOLE DR once daily taken as needed. Despite treatment, the possibility for development of esophagitis in patients cannot be excluded.

Healing of Gastric Ulcers Associated with NSAID Therapy: In patients requiring NSAID therapy, the recommended dose is 20 mg Riva-ESOMEPRAZOLE DR once daily for 4 to 8 weeks. No additional clinical benefit was observed for the 40 mg dose over the 20 mg dose.

Risk-Reduction of Gastric Ulcers Associated with NSAID Therapy: In patients requiring NSAID therapy who are at risk of gastric ulcers, the recommended dose is 20 mg Riva-ESOMEPRAZOLE DR once daily. No additional clinical benefit was observed for the 40 mg dose over the 20 mg dose. Controlled studies did not extend beyond 6 months.

Zollinger-Ellison Syndrome: The dosage in patients with pathological hypersecretory conditions varies with each individual. The recommended initial dosage is 40 mg Riva-ESOMEPRAZOLE DR twice a day. Dosages should then be adjusted to individual patient’s needs and treatment should continue as long as clinically indicated. A small number of patients have been treated with doses up to 80 mg t.i.d. In a clinical study, 90% of patients (19 out of

1. 21) with a hypersecretory condition such as Zollinger-Ellison syndrome had gastric acid outputs appropriately controlled at various doses and were maintained through 12 months (see Clinical Trials; In Patients with Zollinger-Ellison Syndrome). Safety information is limited in doses above 80 mg a day.

Helicobacter pylori Eradication:

In patients with H. pylori-associated active duodenal ulcer: The recommended dose is Riva-ESOMEPRAZOLE DR 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg, all twice daily for seven days. No further treatment with Riva-ESOMEPRAZOLE DR is required to ensure healing and/or symptom control. This dosing regimen can also be known as esomeprazole magnesium 1-2-3 A.

In patients with a history of duodenal ulcer: The recommended dose is Riva-ESOMEPRAZOLE DR 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg, all twice daily for seven days. This dosing regimen can also be known as esomeprazole magnesium 1-2-3 A. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Pediatrics (12-17 years of age)

Treatment of conditions where a reduction of gastric acid secretion is required:

Children (12-17 years of age)

No dose adjustment is required (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Pediatrics).

Reflux esophagitis: The recommended dose in patients with reflux esophagitis is 20 mg or 40 mg Riva-ESOMEPRAZOLE DR once daily for 4 to 8 weeks. Safety studies do not extend beyond 8 weeks.

Nonerosive Reflux Disease (NERD): In patients with heartburn and/or acid regurgitation, without esophagitis, the recommended dose is 20 mg Riva-ESOMEPRAZOLE DR once daily for 2 to 4 weeks. If symptom control is not achieved after 4 weeks of treatment, further investigation is recommended. Safety studies do not extend beyond 8 weeks.

Riva-ESOMEPRAZOLE DR IS NOT RECOMMENDED FOR USE IN CHILDREN

UNDER 12 YEARS OF AGE

Missed Dose

A missed dose should be taken as soon as possible within 12 hours. If more than 12 hours have passed, then the next scheduled dose should be taken at the appropriate time.

Administration

Special Populations

When used in combination with amoxicillin and clarithromycin, please refer to the Product Monographs of these drugs for prescribing information regarding Contraindications, Warnings and Dosing (in elderly and patients with renal and hepatic insufficiency). Patients with Renal Insufficiency: No dose adjustment is required (see WARNINGS AND PRECAUTIONS).

Patients with Hepatic Insufficiency: No dose adjustment is required for patients with mild to moderate hepatic impairment. The daily doses of 20 mg in patients with severe hepatic impairment should not, as a rule, be exceeded (see WARNINGS AND PRECAUTIONS).

Elderly Patients: No dose adjustment is required (see WARNINGS AND PRECAUTIONS).

OVERDOSAGE

Limited information is available on the effects of higher doses in man, and specific recommendations for treatment cannot be given. Experience from a patient who deliberately ingested an overdose of esomeprazole (280 mg), demonstrated symptoms that were transient, and included weakness, loose stools and nausea. Single doses of 80 mg esomeprazole (esomeprazole) have been shown to be uneventful. No specific antidote is known. Esomeprazole is extensively protein-bound and is therefore not readily dialyzable. Treatment should be symptomatic and general supportive measures should be utilized.

The maximum non-lethal oral dose in male and female rats ranged from 240 to 480 mg/kg (see TOXICOLOGY).

When used in combination with antibiotics, the Prescribing Information/Product Monograph for those antibiotics should be consulted.

For management of suspected drug overdose, contact your regional Poison Control Centre immediately.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Esomeprazole delayed release capsules contain esomeprazole (the S-isomer of omeprazole). Esomeprazole is acid labile and therefore is administered orally as granules filled into a capsule.

Esomeprazole magnesium (a substituted benzimidazole), reduces gastric acid secretion through a highly targeted mechanism of action. It is a specific inhibitor of the gastric enzyme H⁺

, K⁺

• ATPase (the proton pump) which is responsible for acid secretion by the parietal cells of the stomach.

Pharmacodynamics

Esomeprazole accumulates in the acidic environment of the parietal cells after absorption, where it is converted into the active form. This active sulphenamide specifically binds the H⁺

,

K⁺

-ATPase (proton pump), to block the final step in acid production, thus reducing gastric acidity. Esomeprazole is effective in the inhibition of both basal acid secretion and stimulated acid secretion.

In healthy male subjects (n=12), repeated administration with 20 mg esomeprazole once daily for 5 days, decreased mean peak acid output after pentagastrin stimulation by 90% when measured 6 to 7 hours after dosing.

The effect of antisecretory therapy can be predicted from the duration of suppression of intragastric acidity to above pH 4.0 achieved by each drug regimen, and the length of treatment.

The antisecretory activity of esomeprazole magnesium was studied in patients with nonerosive reflux disease. Esomeprazole 20 and 40 mg tablets were administered over 5 days and the proportion of time when intragastric pH was >4 over a 24 hour period was assessed on Day 5, as shown in the following table:

Table 5 Effect on Intragastric pH on Day 5 (n=36)

Parameter Esomeprazole 40 mg Esomeprazole 20 mg

% time gastric pH >4* (hours)

coefficient of variation

70% ** (16.8 hours)

26%

53% (12.7 hours)

37%

Median 24 hour pH 4.9 ** 4.1

coefficient of variation 16% 27% * Gastric pH was measured over a 24-hour period

** p<0.01 esomeprazole 40 mg vs. esomeprazole 20 mg

Eradication of Helicobacter pylori: Infection with H. pylori is associated with peptic ulcer disease and is a major factor in the development of gastritis. Approximately 90 to 100% of

patients with duodenal ulcers, and 80% of patients with gastric ulcer, are infected with H. pylori. Treatment with esomeprazole alone has been shown to suppress, but not eradicate H. pylori.

Eradication of H. pylori with triple therapy consisting of esomeprazole and clarithromycin/ amoxicillin for seven days is associated with healing and improvement of symptoms of duodenal ulcers.

Pharmacokinetics

Absorption of esomeprazole in healthy subjects results in peak plasma levels occurring 1 to 2 hours after dosing. The systemic bioavailability is 64% after a single 40 mg dose and 89% after repeated once daily oral administration (40 mg for 5 days). The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight.

Esomeprazole is 97% protein bound and optically stable in vivo, with negligible inversion to the other isomer.

A pharmacokinetic profile of esomeprazole was studied in 36 patients with NERD after repeated once daily administration of 20 mg and 40 mg.

Table 6 Pharmacokinetic Parameters of Esomeprazole After Oral

Administration for 5 days. Mean (%CV)

Parameters Esomeprazole 40 mg Esomeprazole 20 mg

AUC(_tot) (µmol*h/L) 12.6 (42%) 4.2 (59%) C_max (µmol/L) 4.7 (37%) 2.1 (45%)

T_max (h) 1.6 (50%) 1.6 (86%)

t_1/2 (h) 1.5 (32%) 1.2 (37%) Values represent geometric mean except the T_max, which is the arithmetic mean.

Food intake delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Pharmacokinetics in combination with antibiotics: Interactions between esomeprazole (20 mg b.i.d.), amoxicillin (1 g b.i.d.) and clarithromycin (500 mg b.i.d.), were evaluated in a 4-way cross-over study (each study period was 7 days). When given as the triple combination, the bioavailability (AUC and C_max) of amoxicillin and clarithromycin were not significantly changed in healthy volunteers, compared with either drug given alone. The AUC and C_max of the 14-hydroxyclarithromycin metabolite were both increased by 53% during dosing with the triple combination, compared to values following dosing with clarithromycin alone. There were also significant increases in the AUC (two-fold increase) and C_max (39%) values for esomeprazole during concomitant administration with the antibiotic drugs, compared with esomeprazole alone.

Metabolism

Esomeprazole is completely metabolized by the cytochrome P-450 system, mainly in the liver (via CYP 2C19 and CYP 3A4). The major metabolites of esomeprazole (hydroxy and desmethyl metabolites) have no effect on gastric acid secretion. The CYP 2C19 isozyme, which is involved in the metabolism of all available proton pump inhibitors, exhibits polymorphism. Some 3% of Caucasians and 15-20% of Asians lack CYP 2C19 and are termed “poor metabolizers”. At steady state (40 mg for 5 days), the ratio of AUC in poor metabolizers to AUC in the rest of the population is approximately 2. Dosage adjustment of esomeprazole based on CYP 2C19 status is not necessary.

Almost 80% of an oral dose of esomeprazole is excreted as metabolites in urine with the remainder recovered in feces. Less than 1% of the parent drug is found in urine. Total recovery from urine and feces is 92 to 96% within 48 hours of a single oral dose.

Special Populations and Conditions

Pediatrics (12 – 17 years of age)

Children (12-17 years of age): The pharmacokinetics of esomeprazole were studied in 28 pediatric patients with GERD aged 12 to 17 years, in a single centre randomized study. Patients received esomeprazole 20 mg or 40 mg once daily for 8 days. Mean C_max and AUC values of esomeprazole were not affected by body weight or age. More than dose-proportional increases in mean C_max and AUC values were observed between the two groups in the study. Overall, esomeprazole pharmacokinetics in pediatric patients aged 12 to 17 years were similar to those observed in adult patients with NERD.

Table 7 Comparison of pharmacokinetic parameters in 12-17 year olds with

GERD and adults with NERD following esomeprazole daily repeated oral dosing*

Data presented are geometric means for AUC, C_max and t_{1/2 λz} and median value for t_max Duration of treatment for 12 - 17 year olds and adults were 8 days and 5 days, respectively. Data were obtained from two independent studies.

Geriatrics: The metabolism of esomeprazole is not significantly changed in elderly subjects. Following repeated oral dosing with 40 mg esomeprazole in healthy elderly subjects (6 males, 8 females; 71 to 80 years of age), AUC and C_max values measured were similar to those previously measured in young GERD patients (ratio of AUC values in elderly vs. GERD subjects: 1.25; ratio of C_max values: 1.18).

Gender: The AUC and C_max values were slightly higher (13%) in females than in males at steady state. Dosage adjustment based on gender is not necessary.

Hepatic Insufficiency: (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS).

Renal Insufficiency: (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS).

Poor Metabolizers: (see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS).

STORAGE AND STABILITY

Temperature: Store in a dry place at controlled room temperature (15-25°C).

Moisture: Riva-ESOMEPRAZOLE DR (esomeprazole) delayed release capsules are moisture-sensitive and are therefore provided in blister compliance packages, suitable for direct distribution to the patient.

Others: Keep in a safe place out of reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms and Packaging

Riva-ESOMEPRAZOLE DR 20 mg capsules: Hard gelatin capsule, size #4. Cap: Yellow opaque, “20 mg” printed in black; Body: White opaque, “20 mg” printed in black. Each capsule is filled with off-white to grayish spherical beads.

Riva-ESOMEPRAZOLE DR 40 mg capsules: Hard gelatin capsule, size #3. Cap: Yellow opaque, “40 mg” printed in black; Body: Yellow opaque, “40 mg” printed in black.Each capsule is filled with off-white to grayish spherical beads.

The 20 mg capsules are provided in HDPE bottles of 90 capsules and press-through blister compliance strips in cartons of 30.

The 40 mg capsules are provided in HDPE bottles of 90 capsules and press-through blister compliance strips in cartons of 30.

Composition

Riva-ESOMEPRAZOLE DR capsules contain the active ingredient esomeprazole magnesium dihydrate and the following non-medicinal ingredients (listed in alphabetical order): diacetylated monoglycerides, dimethicone emulsion 35%, hydroxypropyl methylcellulose 603,

mannitol, methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30%, polysorbate 80, stearoyl macrogolglycerides, sugar spheres, talc, triethyl citrate. The capsule shell is composed of gelatin, yellow iron oxide and titanium dioxide. The black ink is composed of black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong Ammonia.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name: esomeprazole magnesium dihydrate

Chemical Name: Di-(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-

pyridinyl)methyl]- sulfinyl]-1H-benzimidazole magnesium dihydrate

Molecular Formula: C₃₄H₃₆N₆O₆S₂ Mg•2H₂O

Molecular Mass: 749.15 g/mol (dihydrate)

713.1 g/mol (anhydrous basis)

Structural Formula:

N

CH₃ CH₃

CH₂

OMe

S

O N

N

OMe

2

. Mg²⁺ . 2H₂O

Physicochemical Properties: Esomeprazole magnesium is a white to slightly coloured crystalline powder, containing 2 water molecules of hydration. The solubility in water is 0.3 mg/mL, and the solubility in methanol is initially high, but followed by precipitation of a crystalline dihydrate. The pKa of the benzimidazole (omeprazole base) is 8.8, and that of the pyridinium ion, 4.0.

CLINICAL TRIALS

Comparative Bioavailability Studies

Single dose crossover comparative bioavailability study of Esomeprazole 40 mg Delayed-Release Capsules, was performed versus AstraZeneca Canada Inc.’s Nexium (Delayed-Release Tablets), administered as 1 x 40 mg capsules/tablets in 30 healthy male and female volunteers / fast state. Bioavailability data were measured and the results are summarized in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Riva-Esomeprazole DR (esomeprazole magnesium) 40 mg delayed release capsules (Laboratoire Riva Inc.). ^† Nexium^® (esomeprazole magnesium) 40 mg delayed release tablets (AstraZeneca Canada Inc.) were purchased in Canada.

^§ Expressed as the median (range) only

^€ Expressed as the arithmetic mean (CV%) only

Single dose crossover comparative bioavailability study of Esomeprazole 40 mg Delayed-Release Capsules, was performed versus AstraZeneca Canada Inc.’s Nexium (Delayed-Release Tablets), administered as 1 x 40 mg capsules/tablets in 110 healthy male and female volunteers / fed state. Bioavailability data were measured and the results are summarized in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Riva-Esomeprazole DR (esomeprazole magnesium) 40 mg delayed release capsules (Laboratoire Riva Inc.). ^† Nexium^® (esomeprazole magnesium) 40 mg delayed release tablets (AstraZeneca Canada Inc.) were purchased in Canada.

^§ Expressed as the median (range) only

^€ Expressed as the arithmetic mean (CV%) only

Study demographics and trial design

Reflux Esophagitis

Initial Therapy: A meta-analysis of data from 4 randomized, double-blind clinical trials demonstrated the efficacy of esomeprazole 40 mg in the acute treatment of reflux esophagitis. Healing was observed in over 93% (PP analysis) of patients following 8 weeks of treatment and was associated with symptom relief.

Maintenance of healing of Erosive Esophagitis: For maintenance treatment of reflux esophagitis, esomeprazole 20 mg once daily maintained healing of reflux esophagitis and provided symptom relief in the majority of patients (79-93%) over a 6 month period.

Nonerosive Reflux Disease

In five large, multicentre, randomized, double-blind clinical trials, treatment with esomeprazole 20 or 40 mg daily for 4 weeks was compared to treatment with omeprazole 20 mg daily or placebo, regarding the complete resolution of heartburn in patients with nonerosive reflux disease (i.e. without macroscopic esophagitis). All active treatments were highly successful, safe and well-tolerated. Treatment with esomeprazole (20 or 40 mg) provided patients with significantly more heartburn-free days and nights than placebo.

Maintenance Treatment of NERD (On-demand)

Patients with complete resolution of heartburn following initial treatment for NERD were randomized to double-blind treatment with esomeprazole 40 mg, 20 mg or placebo, once daily when needed to control symptoms of GERD for 6 months. Time to discontinuation due to unwillingness to continue with current therapy was the primary efficacy variable. Esomeprazole (20 and 40 mg) was better than placebo with significantly fewer patients discontinuing treatment and by maintaining sufficient control of heartburn in significantly more patients than placebo treatment.

Table 8 Results of on-demand treatment studies of patients with symptoms of GERD, without macroscopic esophagitis. Proportion of patients unwilling to continue on-demand therapy, ITT analysis.

Esomeprazole 40 mg Esomeprazole 20 mg Placebo

Study 1 (n=721) 11% 8% 42% Study 2 (n=376) 10% - 33%

Study 3 (n=342) - 14% 51%

NSAID Associated Upper GI Ulcers

In clinical trials, treatment with esomeprazole (20 mg or 40 mg) once daily was effective, safe and well-tolerated in combination with continuous NSAID use.

Healing of Gastric Ulcers in Patients Requiring NSAID Therapy, Including COX-2 Selective NSAIDs: Two multicentre, randomized, double-blind, active-controlled clinical trials were undertaken in 809 patients (ITT analysis) for up to 8 weeks to compare the effects of esomeprazole (40 mg or 20 mg qd) against ranitidine (150 mg bid) in the healing of gastric ulcers in patients using non-selective or COX-2-selective NSAIDs. Patients enrolled in these studies had a gastric ulcer greater than or equal to 5 mm in diameter, ranged in age from 18 to 88 (mean age of 58 years) with 32% males and 68% females having a race distribution of 82% Caucasian, 5% Black, 7% Oriental and 12% other. Among these patients 85% were taking non-selective NSAIDs and 15% were on COX-2 selective NSAIDs. H. pylori status of patients at screening was 77% negative and 23% positive.

The results of these two studies are presented below:

Table 9 Observed Gastric Ulcer Healing rates in complete ITT

population regardless of NSAID type.

E20 = esomeprazole 20 qd; E40 = esomeprazole 40 mg qd; R150 = ranitidine 150 mg bid. a chi-square p-value vs. Ranitidine 150 mg bid

b statistically significant vs. R150 (Hochberg adjusted)

Table 10 Observed GU healing status divided by NSAID usage at

Week 4 and Week 8: (ITT pooled population).

E20 = esomeprazole 20 qd; E40 = esomeprazole 40 mg qd; R150 = ranitidine 150 mg bid. a p-value versus R150.

b statistically significant.

Note: Two patients in the R150 group (1 from each study) were not taking any NSAID medication before or during the study and were classified as “No Value,” and were not included in this table. COX-2 selective NSAID is defined as patients who were on COX-2 monotherapy for 4 weeks prior to baseline EGD; Nonselective NSAID is defined as patients who were on any other NSAID medication or a combination therapy of COX-2 selective plus non-selective NSAID medication during the 4 weeks prior to baseline EGD.

Risk-Reduction of Gastric Ulcers Associated with NSAID Therapy, Including COX-2 Selective NSAIDs: In two large multicentre, randomized, double-blind placebo-controlled trials, esomeprazole (40 mg or 20 mg qd) was compared to placebo for the risk reduction of gastric ulcers associated with NSAID therapy in 1378 patients (ITT analysis). Patients enrolled in these studies ranged in age from 21 to 89 (mean age of 65 years) with 29% males and 71% females having a race distribution of 82% Caucasian, 5% Black, 4% Oriental and 8% other. Among these patients 71% were taking non-selective NSAIDs and 29% were on COX-2 selective NSAIDs. H. pylori status of patients at screening was 88% negative, 11% positive and 1% unknown. Patients at risk of an ulcer using either non-selective or COX-2-selective NSAIDs, were treated over a 6 month period. Patients treated with esomeprazole 40 mg or 20 mg had significantly higher estimated ulcer-free rates compared to placebo as shown below.

In both risk-reduction studies an ulcer was defined qualitatively as having; a base (circular or elliptical white or grey-white punched-out defect in the mucosa that could be smooth and regular); a margin (discrete, sharply demarcated, regular, smooth, and usually raised in relation to the ulcer base) and lack of an associated mass lesion or other features suggesting malignancy. Study 13 was considered the pivotal trial due to the fact that quantitative ulcer diameter measurements were recorded. It was demonstrated that esomeprazole 20 and 40 mg

patients had a significant reduction in ulcer (≥ 5 mm) frequency compared to placebo (both p = 0.01). Study 14 was considered supportive as no ulcer diameter measurements accompanied the qualitative ulcer definition in this trial.

Table 11 Proportion of patients without gastric or duodenal ulcer by Month

6 in an ITT population.

E20 = esomeprazole 20 qd; E40 = esomeprazole 40 mg qd

*Log rank test p-value (vs. Placebo)

In Patients with Zollinger-Ellison Syndrome

In an open label clinical trial in 21 patients with a hypersecretory condition such as Zollinger- Ellison syndrome or idiopathic hypersecretion (19 ZES, 2 IH), 90% of all patients (19 of 21) were treated successfully with esomeprazole doses from 40 mg to 80 mg twice daily, with 1 patient receiving 80 mg t.i.d., for up to 12 months. For the trial duration, 14 of 21 patients were maintained and controlled on a esomeprazole dose of 40 mg b.i.d., and 5 patients were maintained and controlled on esomeprazole doses above 80 mg/day. Basal acid levels were maintained well below the targets of ≤10 mEq/h (or ≤5 mEq/h in patients who have undergone previous acid- reducing surgery) in 90% of all patients (19 of

1. 21) on 80 – 240 mg esomeprazole per day. Esomeprazole was generally well tolerated in this patient population (see ADVERSE REACTIONS; Zollinger-Ellison syndrome). Safety information does not extend beyond 1 year for esomeprazole doses 80 mg daily or higher, and was from a limited study population.

In Patients with H. pylori-Associated Active Duodenal Ulcer

Ninety-five to 100% of duodenal ulcer and 80% of gastric ulcer patients are H. pylori-positive, and should be treated with eradication therapy.

Table 12 Results of a Study in Patients With Active Duodenal Ulcer Who Were H.

Pylori-Positive.

Patients with duodenal ulcer, included in the ITT analysis, were assessed for H. pylori status by UBT, HUT® (test and histology pre- and post-treatment, n=433 (ITT analysis).

* Historical data from Losec® (omeprazole) Product Monograph.

In patients with a history of duodenal ulcer

Eradication of H. pylori is associated with long-term remission of peptic ulcer disease. Long- term treatment of these patients with anti-secretory agents is generally not recommended.

Table 13 Results of a Study in Patients With a History of Duodenal Ulcer Who

Were H. Pylori-Positive.

Patients included in the ITT and PP analyses were assessed for H. pylori status by UBT pre- and post- treatment, n=400 (ITT analysis).

In pediatrics (12-17 years of age)

Children (12-17 years of age) with Gastroesophageal Reflux Disease (GERD)

In a multicentre, randomised, double-blind, parallel study (n=149; 89 female, 124 Caucasian, 15 Black, 10 Other) pediatric patients (12-17 years of age) with clinically diagnosed GERD were treated with either esomeprazole 20 or 40 mg once daily for up to 8 weeks to evaluate safety and tolerability. Patients were not endoscopically categorized as to the presence or absence of reflux esophagitis.

The use of esomeprazole in pediatric patients (12 to 17 years of age) for the treatment of GERD is supported by extrapolation of results already included in the currently approved labelling from a) adequate and well-controlled studies in adults that supported the approval of esomeprazole for adults, and additionally from b) safety and pharmacokinetic studies performed in pediatric patients (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions, Pediatrics and ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Pediatrics and CLINICAL TRIALS, Reflux Esophagitis and Nonerosive Reflux Disease).

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamic Data Supporting Oral Clinical Use of Esomeprazole in Adult Patients

Primary Pharmacological Effects

Esomeprazole inhibits the gastric H⁺, K⁺-ATPase, the enzyme identified as the proton pump of the parietal cell. The effect of esomeprazole on acid formation has been compared to that of the racemate, omeprazole, and the other enantiomer (R-omeprazole) in vitro, in isolated rabbit gastric glands and in vivo in rats and dog.. Esomeprazole was shown to inhibit acid secretion to a similar extent as omeprazole, without any significant differences between the 2 compounds in vitro. In in vivo studies in rats, the R-enantiomer showed a statistically significantly greater inhibition of acid output than the racemate omeprazole, which in turn had a statistically significantly greater effect than esomeprazole. This pharmacodynamic (PD) difference reflected a corresponding difference in total systemic exposure, in that the AUC for the R-enantiomer>omeprazole>esomeprazole. No differences were noted in either the PD or the pharmacokinetic (PK) in vivo data in dogs. Thus, the pharmacodynamic effects of esomeprazole and omeprazole are similar at equivalent systemic exposure, and therefore, the PD studies performed with omeprazole can also be considered relevant for esomeprazole.

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 3-5 days of administration. In dogs, a dose of 0.5 µmol/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- 65% when measured 24 hours after dosing at steady state. Once steady-state conditions were reached (after 3-5 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 esomeprazole, 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 esomeprazole 14-140 mg/kg/day resulted in plasma gastrin levels of 140-2400 pg/mL as compared to 75-100 pg/mL in controls. In dogs, high doses of esomeprazole (28 mg/kg/day) produced hypergastrinemia (170-700 pg/mL after food intake), as compared to 53±16 pg/mL in controls. However, no hyperplasia of G-cells was evident in this species.

Secondary Pharmacological Effects

Due to the unique mechanism and specific effect on acid secretion, omeprazole has no significant pharmacodynamic effects unrelated to the inhibition of acid secretion. This property is expected to be shared with esomeprazole.

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 nor on exploratory activity was recorded, suggesting that omeprazole is devoid of sedative or neuroleptic effects.

Pharmacodynamic Data Supporting Oral Clinical Use of Esomeprazole in Pediatric

Patients

No additional pharmacology studies in juvenile animals were necessary.

Pharmacokinetic Data Supporting Oral Clinical Use of Esomeprazole in Adult Patients

Absorption and Distribution

Absorption of esomeprazole is rapid. Peak plasma levels were found within 5 minutes in the rat following duodenal administration, and within 15 minutes in the dog following oral administration. The bioavailability of esomeprazole (34%) was not significantly different from that of omeprazole (38%) in rats. In dogs, the bioavailability of esomeprazole was higher than that of the other enantiomer. Esomeprazole showed enantiomeric stability, with a maximum of 2% of the other enantiomer detected in blood following a single intraduodenal administration of esomeprazole in rats.

In rats, the AUC for the R-enantiomer>omeprazole>esomeprazole at pharmacologically relevant dose levels. However, the difference was less clear at the high dose levels used in the toxicology studies. Higher plasma concentrations of both esomeprazole and omeprazole were

consistently noted in female rats compared to males. Values seen in pregnant rats were of the same order of magnitude as those noted in non-pregnant females. However, exposure in pregnant rabbits after oral administration was relatively low, and thus this species was considered to be less relevant for reproduction toxicity studies on esomeprazole than the rat.

Overall, PK and toxicokinetic (TK) evaluations did not reveal any major differences between esomeprazole and omeprazole with regards to the systemic exposure in dogs. No differences were noted in the C_max and AUC values for esomeprazole and omeprazole in dogs at pharmacologically effective doses. At the higher dose levels used in the toxicity studies, the C_max of esomeprazole tended to be somewhat higher after administration of the same oral dose, but the exposure (AUC) was equivalent. No differences were seen between male and female dogs.

After absorption, omeprazole and esomeprazole are rapidly distributed to extravascular sites, and about 85%-90% 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

The in vitro metabolic disposition of esomeprazole was compared with that of omeprazole in liver microsomal preparations from adult mice, rats, rabbits, dogs and humans. The main metabolites formed did not indicate major differences in the qualitative metabolic disposition between esomeprazole and omeprazole, with respect to species, sex or the structure of metabolites formed.

The excretion and metabolism of esomeprazole was compared to that of omeprazole in vivo, in dogs, following oral administration. Extensive metabolism was confirmed with similar excretion patterns in the urine and feces and with the same pattern of metabolites. All the major metabolites identified following the administration of omeprazole were also found after administration of esomeprazole. Identifiable metabolites constituted about 54% of the total metabolite excretion in 10 hours, and about 12% of the administered dose. There are no differences in excretion routes and recovery between esomeprazole and omeprazole after oral administration to dogs.

Pharmacokinetic Data Supporting Clinical Use of Esomeprazole in Pediatric Patients

The plasma protein binding levels for esomeprazole were similar (about 90%) in neonatal, juvenile and young adult rats. The degree of binding in dogs was about 85% to 90%, and again did not seem to vary with age.

In juvenile rats and dogs, the exposure to esomeprazole was generally comparable between males and females, although there was a slight tendency towards a higher exposure in female

than in male rats at the highest dose level on Dose Day 28. The C_max for esomeprazole was observed between 10 and 60 minutes in juvenile rats and generally at 20 minutes for juvenile dogs. The exposure generally increased more than proportionally to the increase in dose in both juvenile rats and dogs.

The AUC for esomeprazole and omeprazole in juvenile rats and for esomeprazole in juvenile dogs decreased notably with the duration of treatment and/or the age of the animals, resulting in 10-fold lower AUC values after 1 month’s once-daily treatment in rats or 2 or 3 months’ once-daily treatment in dogs, compared to Dose Day 1. The decrease in exposure in dogs was similar, regardless of whether esomeprazole was given once daily or intermittently, once every 14 days. However, when the esomeprazole dosage was increased from once to twice daily dosing from Dose Day 28, both the AUC and C_max following the second daily dose were higher than the values following the first daily dose, on most sampling occasions. Thus, administration of the 2^nd dose resulted in a more than dose-proportional increase in exposure, and also AUC values that were only 3-fold lower on Dose Day 91 compared to Dose Day 1. Thus, increasing the dose from once to twice daily administration of esomeprazole from Dose Day 28 resulted in an exposure on Dose Day 91 that was about 5-fold higher than that attained following once daily administration throughout the study.

An investigation of 6 CYP isoenzyme-specific activities in liver microsomes from juvenile and young adult dogs showed some increase in the activity of EROD (reflecting CYP1A1/2 activity) and also a slight increase in the activity of CZXH (reflecting CYP2E1 activity), after esomeprazole treatment, compared to vehicle-treated animals. However, other CYP isoform activities decreased or were unaffected, and similar changes were seen in both the puppies and young adult dogs treated with esomeprazole once- or twice daily or only intermittently (once every 14 days). In addition, the in vitro intrinsic clearance-rate, half-life and metabolic profiles of esomeprazole in liver microsomes from the dogs were similar, regardless of the gender, treatment/vehicle, dosing regimen or age of the pups. Thus, the increases in EROD and CZXH activities were not reflected in the clearance of esomeprazole in the dog liver microsomes, and it is therefore assumed that the metabolism of esomeprazole is mainly mediated by other CYP isoenzymes.

Human Pharmacology

Pharmacodynamics

When administered once daily for 7 days to healthy subjects defined as extensive metabolizers of omeprazole, 15 mg esomeprazole produced a more pronounced reduction in pentagastrin- stimulated acid output (PAO) compared to a dose of 15 mg omeprazole. The median reduction achieved with esomeprazole treatment was 91% as compared to 64% for omeprazole treatment.

Oral dosing with 5 to 20 mg esomeprazole once daily for 5 days resulted in a rapid and dose- dependent reduction in stimulated gastric acid secretion in healthy subjects.

Table 14 Percent Inhibition (Estimates and 95% CIs) Following Single and

Repeated Doses of Esomeprazole or Omeprazole.

Mean % Inhibition of PAO Estimate (95% Cl)

Single Dose Repeated Doses esomeprazole, 5 mg 14.6 27.8 esomeprazole, 10 mg 29.2 62.1 esomeprazole, 20 mg 45.7 89.9 omeprazole, 20 mg 35.4 78.7

In a three-way cross-over study of 36 male and female patients with heartburn and acid regurgitation (symptoms of GERD), esomeprazole 20 and 40 mg had a dose-dependent effect on intragastric acidity that was significantly greater than that seen with treatment with 20 mg omeprazole, following daily dosing for 5 days (see table below).

Table 15 Percentage of Patients With Intragastric pH >4 Following Repeated

Dosing (5 days) With Esomeprazole or Omeprazole (n=36).

Treatment Percentage of Patients with Intragastric pH >4

At Least 12 h At Least 16 h

Esomeprazole 40 mg 92% 56% Esomeprazole 20 mg 54% 24% omeprazole 20 mg 45% 14%

A similar study (two-way cross-over design) was also undertaken in 115 male and female patients with symptoms of GERD to compare the effects of daily doses of esomeprazole 40 mg versus omeprazole 40 mg on intragastric acidity. The results of this study demonstrated that esomeprazole 40 mg resulted in a significantly greater proportion of time with intragastric pH>4 than omeprazole 40 mg after both one and five days (p<0.001).

Table 16 Percentage of Patients With Intragastric pH >4 Following Repeated

Dosing (5 days) With Esomeprazole or Omeprazole (n=115).

Treatment Percentage of Patients with Intragastric pH >4

At Least 12 h At Least 16 h esomeprazole, 40 mg 88% 56% omeprazole, 40 mg 77% 45%

In a two-way cross-over study of 31 male and female patients with heartburn and acid regurgitation (symptoms of GERD), daily doses of esomeprazole 40 mg resulted in a

significantly greater proportion of time with intragastric pH>4 than daily pantoprazole 40 mg after both one and five days (p<0.001).

Table 17 Percentage of Patients With Intragastric pH >4 Following Repeated

Dosing (5 days) With Esomeprazole or Pantoprazole (n=31).

Treatment Percentage of Patients with Intragastric pH >4

At Least 12 h At Least 16 h

Esomeprazole 40 mg 90% 50% pantoprazole 40 mg 30% 10%

In a two-way cross-over study of 30 male and female healthy volunteers, daily doses of esomeprazole 40 mg resulted in a significantly greater proportion of time with intragastric pH>4 than daily 30 mg lansoprazole after five days (p<0.001).

Table 18 Percentage of Subjects With Intragastric pH >4 Following Repeated

Dosing (5 days) With Esomeprazole or Lansoprazole (n=30).

Treatment Percentage of Subjects with Intragastric pH >4

At Least 12 h At Least 16 h esomeprazole, 40 mg 90% 38% lansoprazole, 30 mg 57% 5%

Other Pharmacodynamic Effects

The effect of esomeprazole on various organ systems has not been investigated. Data taken from clinical studies using omeprazole capsules show that no clinically significant effects attributable to the drug could be found for the following parameters: Endocrine: plasma levels of insulin, C-peptide, glucagon, PTH, 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 esomeprazole, elevated concentrations of alkaline phosphatase, S-ASAT and S-ALAT have been reported.

No clinically significant CNS effects have been recorded.

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

Pharmacokinetics

Esomeprazole undergoes first-pass metabolism, and is completely metabolized by the cytochrome P-450 system (CYP), mainly in the liver. Its metabolism is dependent upon the polymorphically expressed, specific isoform, CYP 2C19 (S-mephenytoin hydroxylase) and CYP 3A4. Less individual variability is seen in the pharmacokinetics of esomeprazole as compared to omeprazole. The influence of CYP 2C19 polymorphism is also less pronounced

for esomeprazole than for omeprazole.

Nine major urinary metabolites have been detected. The two main metabolites have been identified as hydroxyesomeprazole and the corresponding carboxylic acid. Three major metabolites have been identified in plasma: the 5-O-desmethyl- and sulphone derivatives and hydroxyesomeprazole. The major metabolites of esomeprazole have no effect on gastric acid secretion.

Please refer to ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics and DRUG INTERACTIONS for the results of pharmacokinetic studies in special populations and drug interaction studies.

TOXICOLOGY

Toxicology Data Supporting the Oral Use of Esomeprazole in Adult Patients

Single-dose Toxicity

Table 19 Single-dose Toxicity Studies of Esomeprazole.

Species Sex Route Min. Lethal Dose

(mg/kg)

Max. Non-Lethal Dose

(mg/kg)

Rat M p.o.¹ 930 480 F p.o.¹ 480 240

Rat M i.v.² 290 170 F i.v.² 290 170 1 aqueous solution, ² solution in physiological saline

The single dose toxicity of esomeprazole was studied in Wistar rats following oral and i.v. administration and compared to that of omeprazole. The effects of esomeprazole, administered either intravenously or orally, were similar to those previously reported for omeprazole. A small but clear difference in response between the sexes was seen.

The main signs of acute toxicity were reduced motor activity, coupled with changes in respiratory frequency and abdominal respiration. Intermittent clonic convulsions, sometimes associated with dyspnea, increased salivation, cyanosis, tremor, ataxia and/or very reduced motor activity were also seen. Death occurred within 23 hours of oral treatment or 2 hours of i.v. administration.

Repeat-dose Toxicity

The repeat-dose toxicity of esomeprazole was studied in rats (Wistar and Sprague-Dawley) and dogs after oral administration. Rats received oral doses of 14-280 mg/kg, and dogs 0.66-28 mg/kg, for up to 3 months. Esomeprazole has a low systemic toxicity. Some slight

haematological changes indicating a mild microcytic, hypochromic anaemia (possibly due to an iron deficiency) were observed in adult rats, following repeat-dose oral treatment with high doses of esomeprazole or omeprazole. Similar slight changes were seen in pregnant rabbits, but no such changes were noted in esomeprazole-treated dogs. In both rats and dogs, histopathological changes in the stomach at the intermediate and high dose levels (rats: 69 and 280 mg/kg; dogs: 5.5 and 28 mg/kg) consisting of dose-dependent chief cell atrophy, mucosal hyperplasia, and/or focal necrosis of gastric glands, were accompanied by a dose-dependent increase in stomach weight and serum gastrin levels. These changes were expected and consistent with previous observations following treatment with high doses of omeprazole. These effects are the results of gastrin stimulation and/or inhibition of gastric acid secretion.

Reproduction Studies

Slight maternal toxicity was noted in pregnant rats treated orally with esomeprazole or omeprazole at doses of up to 280 mg/kg/day, but no adverse effects could be detected on embryo-foetal survival or development. The systemic exposure to esomeprazole in these animals was substantially higher than that seen in the clinical situation, indicating an adequate margin of safety.

Neither did treatment of pregnant rabbits with esomeprazole or omeprazole indicate any potential for disturbance of embryo-foetal development. However, severe and dose-related maternal toxicity was noted at relatively low doses and exposure of esomeprazole/omeprazole, resulting in some minor litter effects (a slight reduction in fetal weight and a small increase in the incidence of minor skeletal defects at doses of 26 and 86 mg/kg/day). Although exposure to esomeprazole was relatively low in many of the does, the highest dose level used could not be increased due to this maternal toxicity.

Mutagenicity

Esomeprazole was not mutagenic in an in vitro Ames Salmonella test, but was clastogenic in an in vitro chromosome aberration test in peripheral human lymphocytes. When compared head to head in another study in peripheral human lymphocytes, esomeprazole, omeprazole, the R- enantiomer of omeprazole and lansoprazole induced the same type and degree of chromosome aberrations. Esomeprazole did not show any evidence of mutagenic potential in vivo in a mouse micronucleus test or in a chromosome aberration test in rat bone marrow in spite of extensive exposure.

Carcinogenicity

An 18-month oral study was conducted in mice at doses of 14, 44 and 140 mg/kg/day of omeprazole. 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 sub-mucosa. 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. 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 hypogastrinemia and 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.

An additional long-term (24 months) toxicity study of omeprazole in female rats (1.8-14 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 (1.8-140 mg/kg/day). In rats given omeprazole 14 mg/kg/day for 12 months, no carcinoids were found, and the ECL-cell hyperplasia seen after 12 months recovered to normal during the next 12 months of no treatment.

No carcinoids were found in the mice carcinogenicity study over 18 months, in a 6-month carcinogenicity bioassay conducted with omeprazole in p53± heterozygous and C57BL/6 (background strain) mice at dose levels of up to 830 mg/kg/day, or in dogs following administration of 0.17 mg/kg/day omeprazole for 7 years.

Treatment with esomeprazole for up to 1 year in more than 800 patients resulted in moderate increases in serum gastrin levels. However, no significant pathological changes in the gastric oxyntic endocrine cells were observed.

Toxicology Data Supporting the Oral Use of Esomeprazole in the Pediatric Population

There was no unexpected toxicity and/or other effects following esomeprazole treatment of rats or dogs from the neonatal period, during suckling and beyond weaning, compared to those previously observed in adult animals.

CNS signs and mortality were noted at the beginning of the dosing period at the highest esomeprazole dose levels in both neonatal/juvenile rats and dogs. This effect can be attributed to the high esomeprazole plasma levels attained in this age of animal. These plasma levels were within the range at which CNS signs (but not mortality) have previously been seen in adult animals, but additional effects such as repeated dehydration/starvation in the affected neonatal

animals probably also contributed to the poor general condition and mortality in these young individuals.

As in the adult rats and pregnant rabbits, a mild microcytic, hypochromic anaemia (which was probably due to an iron deficiency) was observed in both the esomeprazole-treated juvenile rats and dogs. This reaction was more pronounced in the young animals compared to that seen previously in adult animals, was shown to be dose- and time-related, and was fully reversible by the end of the dose-free recovery period.

The low level of changes in the number of ECL-cells in the gastric mucosa that were seen in both the juvenile rats and dogs, and the complete lack of other gastric histopathological changes, indicate that neonatal/juvenile rats and dogs are not more susceptible to proliferative changes in the gastric mucosa following esomeprazole treatment, compared to adult animals.

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    November 17, 2011, Control Number: 149266.