CONTOUR (Esomeprazole magnesium.)


PRESENTATION: Cap (enteric-coated microgranules) 40 mg x 14's.
ACTIONS: Pharmacology: Pharmacodynamics: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. lt is a specific inhibitor of the acid pump (proton pump) in the parietal cell. Site and Mechanism of Action: Esomeprazole is a weak base. lt is concentrated and converted to the active sulphonamide form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+/K+-ATPase, the acid pump; the final step in acid production thus reduces both basal and stimulated acid secretions. Effect on Gastric Acid Secretion: After oral dosing with esomeprazole 20 and 40 mg the onset of effect occurs within '1 hr. The effect on gastric acid secretion is dose-related up to a daily dose of 20-40 mg. After 5 days of oral dosing with esomeprazole 20 and 40 mg, intragastric pH >4 was maintained for a mean time of 1 3 and 1 7 hrs, respectively over 24 hrs. ln symptomatic GERD patients, the proportion of patients maintaining an intragastric pH >4 for at least 8, 12 and 16 hrs respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%. Therapeutic Effects of Acid lnhibition: Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks and in 93% after 1 week. Ten days of treatment with esomeprazole 40 mg once daily and appropriate antibiotics, results in successful eradication of Helicobacter pylori in approximately 90% of patients. After eradication treatment for 10 days, there is no need for subsequent monotherapy with antisecretory drugs for effective, ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
Pharmacokinetics: Absorption: Esomeprazole is acid labile and is administered orally as enteric-coated microgranules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hrs after oral dose. The absolute bioavailability is 64% on day 1 after a single dose of 40 mg and increases to approximately 90% on day 5 after repeated once daily administration. For esomeprazole 20 mg, the corresponding values are 50% and 68% respectively. Food intake both delays and decreases the absorption of esomeprazole, although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Distribution: The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprzole is 97% plasma protein bound.
Metabolism: Esomeprazole is extensively metabolized in the liver by the cytochrome P-450 (CYP) enzyme system. The major part of esomeprazole's metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy- and desmethylmetabolites of esomeprazole. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite, the main metabolite in plasma. The following parameters reflect mainly the pharmacokinetics in individuals with a functional CYP2C'1 9 enzyme, extensive metabolisers. Total plasma clearance is about 17 L/hr after a single dose and about 9 L/hr after repeated administration.
The plasma elimination t1/2  is about 1.3 hrs after repeated once-daily dosing. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is due to a decrease of first-pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. CYP2O19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15-20% of Asians lack CYP2Cl9 and are termed poor metabolisers. At steady state, the ratio of AUC in poor metabolisers to AUC in the rest of the population (extensive metabolisers) is approximately 2.
Following administration of equimolar doses, the S-and R-isomers are metabolised differently by the liver, resulting in the higher plasma levels of the S-than of the R-isomer. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration. Excretion; The major metabolites of esomeprazole have no effect on gastric acid secretion. Approximately 80% of an oral dose of Contour is excreted as inactive metabolites in the urine, the remainder in the faeces. Less than 1 % of the parent drug is found
in urine. Special Patient Populations: Elderly: The AUC and
Cmax values were slightly higher (25% and 18% respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment based on age is not necessary. The metabolism of Contour is not significantly changed in elderly subjects (71 -80 years).
Gender: 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.
Hepatic lnsufficiency: Contour in patients with mild and moderate hepatic insufficiency, the AUCs were within the range that could be expected in patients with normal Liver functions. ln patients with severe hepatic insufficiency the AUCs were 2-3 times higher than in patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency. A dose of 20 mg should not be exceeded in patients with severe hepatic dysfunction.
Renal insufficiency: The pharmacokinetics of Contour in patients with renal impairment are not expected to be altered to healthy volunteers as <1% of esomeprazole is excreted unchanged in urine. Dose adjustment is not required in patients with impaired renal function.
INDICATIONS: Treatment of Acid Peptic Disorders: Benign gastric ulcer, duodenal ulcer. Gastroesophageal Reflux Disease (GERD): Symptomatic treatment of GERD. Long-term management of patients with healed esophagitis to prevent relapse. NSAIDS Associated Ulcers: Appropriate antibacterial therapeutic regimen in combination for eradication of Helicobacter pylori and healing of Helicobacter pylori associated duodenal ulcer. Prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.
DOSAGE & ADMINISTRATION: Contour capsules should be swallowed whole with liquid at least1 hr before meal. The capsules should not be chewed or crushed. For patients who have difficulty in swallowing the capsules, Contour can also be dispersed in 1/2, glass of noncarbonated water. No other liquids should be used as the enteric coating may be dissolved.
Stir until the enteric-coated microgranules disintegrate and drink the liquid with the pellets immediately or within 30 min. Rinse the glass with 1/2, glass of water and drink. Antacids may be used while taking Contour. Gastroesophageal Reflux Disease (GERD): Treatment of Erosive Reflux Esophagitis: 40 mg once daily for 4-8 weeks. An additional 4-8 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms. Long-Term Management of Patients with Healed Esophagitis to Prevent Relapse: 20 mg once daily. Symptomatic Treatment of GERD: 20 mg once daily in patients without esophagitis. lf symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen by taking 20 mg once daily, when needed. Appropriate Antibacterial Therapeutic Regimen in Combination for Eradication of Helicobacter pyloti: Prevention of Relapse of Peptic Ulcers in Patients with Helicobacter pylori Associated
Ulcers: 40 mg once daily with amoxicillin 1 g and clarithromycin 500 mg, twice daily for 10 days.
CONTRAINDICATIONS: Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of Contour
WARNINGS: ln the presence of any alarm symptom
(e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, haematomesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole like all antisecretory drugs may alleviate symptoms and delay diagnosis.
PRECAUTIONS: General: Patients on long term treatment (particularly those treated for >1 year should be kept under regular surveillance. Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing
Contour for on-demand therapy, the implications for interactions with other pharmaceuticals should be considered. When prescribing Contour for eradication of Helicobacter pylorias with other antisecretory drugs, possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple  therapy is used in patients concurrently taking other drugs metabolized via CYP3A4 e.g., cisapride. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take Contour.
Use in pregnancy & Lactation: Contour is classified in FDA Pregnancy Category B. For esomeprazole no clinical data on exposed pregnancies are available. Animal studies with esomeprzole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women. It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: Contour should not be used in children since no data is available.
ADVERSE REACTIONS: The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole. None was found to be dose-related. Common (>1/100, < l/10): Headache, abdominal pain, diarrhoea, flatulence, nausea, vomiting, constipation. Uncommon (>1/1 000, <1/100): Dermatitis, pruritus, urticaria, dizziness, dry mouth. The following adverse drug reactions have been observed for the racemate (omeprazole) and may occur with esomeprazole:
Central and Peripheral Nervous System: Paresthesia, somnolence, insomnia, vertigo, reversible mental confusion, agitation, aggression, depression and hallucinations, predominantly in severely ill patients.
Endocrine: Gynaecomastia.
Gastrointestinal: Stomatitis and Gl candidiasis.
Haematological: Leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.
Hepatic: lncreased liver enzymes, encephalopathy in patients with preexisting severe liver disease; hepatitis with or without jaundice, hepatic failure.
Musculoskeletal: Arthralgia, muscular weakness and myalgia.
Skin: Rash. photosensitivity,erythema  multiforme, Stevens-Johnson syndrome. toxic epidermal necrolysis, alopecia. Other: Malaise, hypersensitivity reactions e.g., angioedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock, increased sweating, peripheral
edema, blurred vision, taste disturbance and hyponatraemia.
INTERACTIONS: Effects of Esomeprazole on the Phamacokinetics of Other Drugs: The decreased intragastric acidity during treatment with esomeprzole, might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.
Contour inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19 e.g., diazepam, citalopram, imipramine, clomipramine, phenytoin, etc, the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on-demand therapy. Concomitant administration of esomeprazole 30 mg resulted in a 45% decrease in clearance of the CYP2C'l 9 substrate diazepam. Concomitant administration of esomeprazole 40 mg resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. lt is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.
Contour has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin, quinidine or warfarin. Effects of Other Drugs on the Pharmacokinetics of
Contour: Contour is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to esomeprazole. Dose adjustment of esomeprazole is not required.

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