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3/23/2001

Omeprazole Isomer Approved by FDA

Cheryl A. Thompson

AstraZeneca has received FDA approval to market esomeprazole (Nexium [PDF]), the S-isomer of omeprazole, for some—but not all—of the same indications held by the racemic proton-pump inhibitor.

The new product is indicated for treatment of gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and, in combination with amoxicillin and clarithromycin, for eradication of Helicobacter pylori to reduce the risk of recurrent duodenal ulcer. Unlike omeprazole, esomeprazole is not indicated for treatment of active benign gastric ulcer or pathological hypersecretory conditions or as part of a two-drug regimen to eradicate H. pylori.

Compared with omeprazole, esomeprazole has greater systemic bioavailability after a single dose and a longer half-life; slightly more of the isomeric drug is bound to plasma proteins, and more of an oral dose is excreted as inactive metabolites. The liver differentially metabolizes the two isomers of omeprazole, resulting in higher plasma levels of esomeprazole than the R-isomer. Metabolism of esomeprazole occurs primarily via cytochrome P-450 (CYP) isoenzyme 2C19, with the remainder handled by CYP 3A4.

The efficacy of esomeprazole 20 or 40 mg daily in healing erosive esophagitis was compared with that of omeprazole 20 mg/day in four multicenter, double-blind, randomized studies involving more than 6700 patients with GERD. Higher healing rates were reported for the esomeprazole groups than the omeprazole groups, but these differences were not significant for every comparison. In the four studies, half of the patients assigned to the higher esomeprazole dosage reported sustained resolution of heartburn within five days; the median time to relief for the other patients was at least seven days.

In two multicenter, double-blind studies, 693 patients whose erosive esophagitis had healed were randomly assigned to treatment with esomeprazole 10, 20, or 40 mg/day or placebo for six months. Similar percentages of patients in the 20- and 40-mg/day groups remained in remission at month 6; the results for all of the esomeprazole groups were significantly better than for the placebo group.

Esomeprazole 20 and 40 mg/day was compared with placebo in two multicenter, randomized, double-blind studies involving 717 patients with GERD but not erosive esophagitis. During follow-up visits at the end of weeks 1, 2, and 4, significantly higher percentages of the esomeprazole-treated patients reported no symptoms of heartburn than did the patients assigned to placebo.

The efficacy of esomeprazole–antibiotic regimens in eradicating H. pylori from patients with duodenal ulcer disease was evaluated in two multicenter, randomized, double-blind studies. Of 448 patients in one study, about 80% of those who received esomeprazole, amoxicillin, and clarithromycin for 10 days were free of H. pylori four weeks later, compared with about 54% of patients who received only esomeprazole and clarithromycin. In the second study, involving 98 patients, the triple-drug regimen achieved results similar to those in the first study; esomeprazole alone eradicated H. pylori in 5% of the patients.

Unlike omeprazole, esomeprazole does not have clinically important interactions with phenytoin or warfarin. The clinical relevance of esomeprazole’s potential to interfere with CYP 2C19, which metabolizes diazepam, is unclear. Because esomeprazole inhibits gastric acid secretion, the drug may interfere with the absorption of ketoconazole, iron salts, digoxin, and other substances whose oral bioavailability greatly varies with changes in gastric pH.

Among the patients in the four studies of esomeprazole for healing of erosive esophagitis, the most frequently reported adverse events were headache and diarrhea. Other gastrointestinal adverse events occurred in less than 1% of the patients and similar rates between the esomeprazole and omeprazole groups.

The recommended esomeprazole regimens for treating GERD are as follows: for healing erosive esophagitis, 20 or 40 mg/day for four to eight weeks, with the option of an additional four to eight weeks if needed; for maintenance healing of erosive esophagitis, 20 mg/day (controlled studies stopped after six months of treatment); and for relief of symptoms, 20 mg/day for four weeks, with the option of four to eight more weeks if needed. Therapy to eradicate H. pylori consists of esomeprazole 40 mg daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily, all taken for 10 days. Patients with severe liver impairment should not take more than 20 mg of esomeprazole per day.

Nexium is supplied as 20- and 40-mg delayed-release amethyst capsules. The two strengths can be differentiated by the "20 mg" or "40 mg" printed in yellow on the capsule body. Doses of esomeprazole should be taken at least one hour before meals. The capsules and enteric-coated drug pellets inside should not be chewed or crushed; however, the contents of a capsule may be mixed with one tablespoonful of applesauce and swallowed immediately. Exposure to tap water, orange juice, apple juice, or yogurt does not harm the pellets.