Nexium

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

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 or itraconazole) must be taken into account when they are co-administered with esomeprazole.

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.

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).

Concomitant administration of NEXIUM (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.

Concomitant administration of 40 mg NEXIUM (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).

Concomitant administration of 40 mg NEXIUM (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 NEXIUM versus other drugs indicate that daily doses of 40 mg NEXIUM, 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†).

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, warfarin, quinidine or cisapride{†No longer marketed in Canada.}.

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

No dose adjustment is required (see Warnings and Precautions).

No dose adjustment is required (see Warnings and Precautions and Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Pediatrics (1-17 Years of Age)).

For the long-term treatment of patients whose reflux esophagitis has been healed with acid suppression therapy, the recommended dose is 20 mg NEXIUM once daily. Controlled studies do not extend beyond 6 months.

In patients requiring NSAID therapy, the recommended dose is 20 mg NEXIUM once daily for 4 to 8 weeks. No additional clinical benefit was observed for the 40 mg dose over the 20 mg dose.

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 NEXIUM once daily taken as needed. Despite treatment, the possibility for development of esophagitis in patients cannot be excluded.

The recommended dose is NEXIUM 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg, all twice daily for seven days. No further treatment with NEXIUM is required to ensure healing and/or symptom control. This dosing regimen can also be known as NEXIUM 1-2-3 A.

The tablets should be swallowed whole with sufficient water.

In patients requiring NSAID therapy who are at risk of gastric ulcers, the recommended dose is 20 mg NEXIUM 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.

The contents of each sachet should be emptied into a container containing 1 tablespoon (15 mL) of water. Stir the contents and leave for a few minutes to thicken. Stir again and drink within 30 minutes. If any material remains after drinking, add more water stir and drink immediately.

The recommended dose in patients with reflux esophagitis is 20 mg or 40 mg NEXIUM once daily for 4 to 8 weeks. Safety studies do not extend beyond 8 weeks.

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

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).

The recommended dose is NEXIUM 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg, all twice daily for seven days. This dosing regimen can also be known as NEXIUM 1-2-3 A. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

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.

The dosage in patients with pathological hypersecretory conditions varies with each individual. The recommended initial dosage is 40 mg NEXIUM 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 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. Safety information is limited in doses above 80 mg a day.

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).

In patients with heartburn and/or acid regurgitation, without esophagitis, the recommended dose is 20 mg NEXIUM 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.

No dose adjustment is required (see Warnings and Precautions).

constipation, defecation urge, duodenitis, epigastric pain, eructation, gastric retention, gastric ulcer, dry mouth, mucosal discolouration GI, frequent stools, vomiting.

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, intestinal nephritis, muscular weakness and gynecomastia have been reported.

As of 25 July 2007, AstraZeneca’s post-marketing safety database has received 28 medically confirmed case reports with 59 adverse events in children between 1 and 11 years of age. All cases constituted off-label use. An overall assessment of the adverse events reported in children ages 1-11 years raised no safety concerns with esomeprazole treatment in this age group.

As of 25 June 2007, AstraZeneca’s post-marketing safety database has received 48 medically confirmed case reports with 84 adverse events in children between 12 and 17 years of age. 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.

See Adverse Reactions, Post-Market Adverse Drug Reactions, and Warnings and Precautions, Carcinogenesis and Mutagenesis.

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.

hepatic enzymes increased NOS, increased AST, increased ALT.

Adverse reactions have been recorded during a clinical investigation in 109 pediatric patients (1-11 years of age) exposed to NEXIUM. There was an increase number of adverse events reported (irrespective of causality) in the >20 kg treatment groups (mean age of 8.4 years old) versus the <20 kg treatment group (mean age 2.3 years old), however there was no difference in the character of the adverse events reported by age group or dosing group. The most common reactions (irrespective of causality) which occurred with a frequency of >1% in clinical studies included vomiting, pyrexia, diarrhea and cough. The most frequently reported (at least 1%) treatment-related adverse events were diarrhea (2.8%), headache (1.9%) and somnolence (1.9%). No new safety concerns were identified.

In this study there were some inconsistent and minor changes (i.e. <5 mmHg) in blood pressure (BP) which were not considered to be a drug effect. For most dosing groups there was a slight increase in mean systolic and diastolic BP values (<5 mmHg) while for the 20 mg dosing group there was a slight decrease in mean systolic BP (<1 mmHg). Overall, the mean BP values remained within normal limits. The interpretation of these inconsistent and minor changes is uncertain due to the lack of a placebo arm in this study.

No clinically important changes or trends were noted over time in clinical chemistry that were different from those already listed from adult studies (see Adults, Abnormal Hematologic and Clinical Chemistry Findings).

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 AST, increased ALT, 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.

muscular weakness.

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 NEXIUM 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.

anorexia, increased appetite, insomnia, sleep disorder.

dehydration, weight decrease, weight increase.

In clinical studies, a total of 446 patients received NEXIUM 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%), ALT 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 NEXIUM is used in combination with amoxicillin and clarithromycin, the Product Monographs for those agents must be consulted and followed.

paresthesia.

GI neoplasm.

NEXIUM (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 NEXIUM. Additionally >1200 adult subjects/patients were exposed to NEXIUM 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 NEXIUM.

Adverse reactions have been recorded during a clinical investigation in 109 pediatric patients (1-11 years of age) exposed to NEXIUM. Among reactions which occurred with a frequency of >1% in clinical studies, only diarrhea, headache and somnolence are associated with the use of NEXIUM. 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 NEXIUM. The treatment related adverse event profile was found to be consistent with that seen in adults.

dermatitis, pruritus and urticaria.

hyponatremia.

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 NEXIUM 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.

herpes simplex.

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

hepatic encephalopathy.

anemia, leukopenia, thrombocytopenia.

NEXIUM (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).

NEXIUM (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{*Note: Superiority of NEXIUM 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 analysed in this subgroup.}-associated gastric ulcers

  
  

• reduction of risk of NSAID-associated gastric ulcers

  
  

• treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome

  
  

• H. pylori eradication

  
  

NEXIUM, in combination with clarithromycin and amoxicillin, is indicated for the treatment of patients with duodenal ulcer disease associated with H. 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.

Each pink, oblong and biconvex, delayed-release tablet, engraved with “40 mg” on one side and “” on the other side, contains: esomeprazole 40 mg equivalent to esomeprazole magnesium trihydrate 44.5 mg. Nonmedicinal ingredients: cellulose microcrystalline, crospovidone, glyceryl monostearate, hydroxypropylcellulose, hypromellose, iron oxide, magnesium stearate, methacrylic acid ethylacrylate copolymer, polyethylene glycol, polysorbate, sodium stearyl fumarate, sugar spheres, synthetic paraffin, talc, titanium dioxide and triethyl citrate. Press-through blister compliance strips, cartons of 30 and 60. HDPE bottles of 100.

Each light pink, oblong and biconvex, delayed-release tablet, engraved with “20 mg” on one side and “” on the other side, contains: esomeprazole 20 mg equivalent to esomeprazole magnesium trihydrate 22.3 mg. Nonmedicinal ingredients: cellulose microcrystalline, crospovidone, glyceryl monostearate, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, methacrylic acid ethylacrylate copolymer, polyethylene glycol, polysorbate, sodium stearyl fumarate, sugar spheres, synthetic paraffin, talc, titanium dioxide and triethyl citrate. Press-through blister compliance strips, cartons of 30.

Each unit-dose sachet of fine, pale yellow, delayed release granules for oral suspension contains: esomeprazole 10 mg. Brownish granules may also be visible. Nonmedicinal ingredients: citric acid, crospovidone, dextrose, glycerol monostearate, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, methacrylic acid copolymer type C, polysorbate, sugar spheres, talc, triethyl citrate and xanthan gum. Cartons of 30.

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).

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 NEXIUM based on CYP 2C19 status is not necessary.

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 NEXIUM (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 NEXIUM on serum gastrin concentrations was evaluated in approximately 2700 patients in clinical trials up to 8 weeks and in over 1300 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.

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 C. 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 C. difficile colitis.

Concomitant administration with atazanavir or nelfinavir is not recommended (see Drug Interactions).

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).

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.

The clinical documentation for NEXIUM does not support the need for routine laboratory monitoring of response to therapy. (See Warnings and Precautions, Carcinogenesis and Mutagenesis for effects of NEXIUM on serum gastrin levels and Adverse Reactions, Post-Market Adverse Drug Reactions for effects on liver functioning.)

The use of NEXIUM in pediatric patients (1 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 NEXIUM for adults, and additionally from b) safety and a pharmacokinetic study performed in pediatric patients (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Pediatrics (1-17 Years of Age) and Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Pediatrics (1-17 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 NEXIUM have not yet been established in pediatric patients <1 years of age.

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

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

The metabolism of NEXIUM is not significantly changed in elderly subjects. Following repeated oral dosing with 40 mg NEXIUM 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.

NEXIUM (esomeprazole) delayed release tablets and delayed release granules for oral suspension are moisture-sensitive and are therefore provided in blister compliance packages and aluminum sachets, suitable for direct distribution to the patient.

Store in a dry place at controlled room temperature (15-30°C).

Keep in a safe place out of reach of children.

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.

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 NEXIUM 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.

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

(See Dosage and Administration and Warnings and Precautions.)

The metabolism of NEXIUM is not significantly changed in elderly subjects. Following repeated oral dosing with 40 mg NEXIUM 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).

(See Dosage and Administration and Warnings and Precautions.)

NEXIUM (esomeprazole) delayed release tablets and granules for oral suspension contain esomeprazole (the S-isomer of omeprazole). Esomeprazole is acid labile and therefore is administered orally as enteric-coated granules compressed into a tablet or as enteric-coated granules in an oral suspension.

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.

(See Dosage and Administration and Warnings and Precautions.)

(See Dosage and Administration and Warnings and Precautions.)

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 NEXIUM alone has been shown to suppress, but not eradicate H. pylori.

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

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.

Comparison of Pharmacokinetic Parameters in 12-17 Year-olds with GERD and Adults with NERD Following Esomeprazole Daily Repeated Oral Dosing^a