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NEXIUM (esomeprazole magnesium trihydrate) 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

  
  

• 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.

• Hypersensitivity to esomeprazole, substituted benzimidazoles or any of the components of this medication (see Dosage Forms, Composition and Packaging).

  
  

• When used for eradication of H. pylori, the contraindications for amoxicillin and clarithromycin as found in the corresponding Product Monographs should be taken into consideration.

  
  

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.

Nexium 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 NEXIUM 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.

Nexium Special Populations

The safety of NEXIUM (esomeprazole magnesium trihydrate) in pregnancy has not been established. NEXIUM tablets 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 tablets should not be given to nursing mothers unless its use is considered essential.

The safety and effectiveness of NEXIUM tablets in children have not yet been established.

The metabolism of NEXIUM (esomeprazole magnesium trihydrate) 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 Cmax 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 Cmax values: 1.18). Therefore, dose adjustment is not required in the elderly.

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

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).

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 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.

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.)

NEXIUM (esomeprazole magnesium trihydrate) 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 patients exposed to NEXIUM. Additionally >1200 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.

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.

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

asthenia, back pain.

anemia, leukopenia, thrombocytopenia.

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

hepatic enzymes increased NOS, increased AST, increased ALT.

dehydration, weight decrease, weight increase.

GI neoplasm.

dizziness, headache, hyperesthesia, vertigo.

anorexia, increased appetite, insomnia, sleep disorder.

herpes simplex.

rash.

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.

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.

dermatitis, pruritus and urticaria.

paresthesia.

malaise.

hyponatremia.

muscular weakness.

hepatic encephalopathy.

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

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.

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.

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).

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†).

Concomitant administration of esomeprazole may reduce the plasma levels of atazanavir.

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.

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

As demonstrated with other PPIs, prolonged use may impair the