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In over 1, 000 patients treated with NEXIUM (10, 20 or 40 mg/ day) up to 6-12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa. Endocrine Effects NEXIUM had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of NEXIUM on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. Text Continues Below
Microbiology Esomeprazole magnesium, amoxicillin and clarithromycin triple
therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections as described in the Clinical Studies and INDICATIONS AND USAGE sections. Helicobacter Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined. Pretreatment Resistance Clarithromycin pretreatment resistance rate (MIC 1 µg/ mL) to H. pylori was 15% (66/ 445) at baseline in all treatment groups combined. A total of >99% (394/ 395) of patients had H. pylori isolates which were considered to be susceptible (MIC 0.25 µg/ mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC= 0.5 µg/ mL. Clarithromycin Susceptibility Test Results and Clinical/ Bacteriologic Outcomes: The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in the table below: Clarithromycin Susceptibility Test Results and Clinical/ Bacteriological Outcomes a for Triple Therapy Ð (Esomeprazole magnesium 40 mg once daily/ amoxicillin 1000 mg twice daily/ clarithromycin 500 mg twice daily for 10 days) Clarithromycin H. pylori H. pylori positive Pretreatment negative (Not Eradicated)
Results (Eradicated) Post-treatment susceptibility results
S b I b R b No MIC
Susceptible b 182 162 4 0 2 14
Intermediate b 1 1 0 0 0 0
Resistant b 29 13 1 0 13 2
a Includes only patients with pretreatment and post-treatment
clarithromycin susceptibility test results b Susceptible (S) MIC 0.25 µg/ mL, Intermediate (I) MIC= 0.5 µg/ mL, Resistant (R) MIC 1.0 µg/ mL Patients not eradicated of H. pylori following esomeprazole magne-sium/ amoxicillin/ clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen. Amoxicillin Susceptibility Test Results and Clinical/ Bacteriological Outcomes In the esomeprazole magnesium/ amoxicillin/ clarithromycin clinical trials, 83% (176/ 212) of the patients in the esomeprazole magnesium/ amoxicillin/ clarithromycin treatment group who had pretreatment amoxicillin susceptible MICs ( 0.25 µg/ mL) were eradicated of H. pylori, and 17% (36/ 212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin. Susceptibility Test for Helicobacter pylori The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. One to three microliters of an inoculum equivalent to a No. 2 McFarland stan-dard (1 x 10 7 Ð 1 x 10 8 CFU/ mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood ( 2 weeks old).
The agar dilution plates are incubated at 35° C in a microaerobic environment produced by a gas generating system suitable for Campylobacter. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria: Clarithromycin MIC (µg/ mL) a Interpretation
0.25 Susceptible (S)
0.5 Intermediate (I)
1.0 Resistant (R)
Amoxicillin MIC (µg/ mL) a, b Interpretation
0.25 Susceptible (S)
a These are breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods. b There were not enough organisms with MICs >0.25 µg/ mL to determine a resistance breakpoint. Standardized susceptibility test procedures require the use of labora-tory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values: Microorganism Antimicrobial Agent MIC (µg/ mL) a
H. pylori ATCC Clarithromycin 0.016 Ð 0.12 43504 (µg/ mL) H. pylori ATCC Amoxicillin 0.016 Ð 0.12 43504 (µg/ mL)
a These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods. Clinical Studies Healing of Erosive Esophagitis The healing rates of NEXIUM 40 mg, NEXIUM 20 mg, and omeprazole 20 mg (the approved dose for this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates at weeks 4 and 8 were evaluated and are shown in the table below: Erosive Esophagitis Healing Rate (Life-Table Analysis)
No. of Significance Study Patients Treatment Groups Week 4 Week 8 Level* 1 588 NEXIUM 20 mg 68.7% 90.6% N. S. 588 Omeprazole 20 mg 69.5% 88.3%
2 654 NEXIUM 40 mg 75.9% 94.1% p <0.001 656 NEXIUM 20 mg 70.5% 89.9% p <0.05
650 Omeprazole 20 mg 64.7% 86.9%
3 576 NEXIUM 40 mg 71.5% 92.2% N. S. 572 Omeprazole 20 mg 68.6% 89.8% 4 1216 NEXIUM 40 mg 81.7% 93.7% p <0.001 1209 Omeprazole 20 mg 68.7% 84.2%
*log-rank test vs omeprazole 20 mg N. S. = not significant (p > 0.05).
In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were
evaluated and are shown in the table below: Sustained Resolution * of Heartburn (Erosive Esophagitis Patients)
Cumulative Percent # with Sustained Resolution
No. of Significance Study Patients Treatment Groups Day 14 Day 28 Level * 1 573 NEXIUM 20 mg 64.3% 72.7% N. S. 555 Omeprazole 20 mg 64.1% 70.9%
2 621 NEXIUM 40 mg 64.8% 74.2% p <0.001 620 NEXIUM 20 mg 62.9% 70.1% N. S.
626 Omeprazole 20 mg 56.5% 66.6%
3 568 NEXIUM 40 mg 65.4% 73.9% N. S. 551 Omeprazole 20 mg 65.5% 73.1% 4 1187 NEXIUM 40 mg 67.6% 75.1% p <0.001 1188 Omeprazole 20 mg 62.5% 70.8%
* Defined as 7 consecutive days with no heartburn reported in daily patient
diary. # Defined as the cumulative proportion of patients who have reached the start of sustained resolution *log-rank test vs omeprazole 20 mg
N. S. = not significant (p > 0.05).
In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heart-burn) was 5 days for NEXIUM 40 mg, 7Ð 8 days for NEXIUM 20 mg and 7Ð 9 days for omeprazole 20 mg. There are no comparisons of 40 mg of NEXIUM with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of erosive esophagitis. Long-Term Maintenance of Healing of Erosive Esophagitis Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate NEXIUM 40 mg (n= 174), 20 mg (n= 180), 10 mg (n= 168) or placebo (n= 171) once daily over six months of treatment. No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg. The percentage of patients that maintained healing of erosive esophagitis at the various time points are shown in the figures below: Maintenance of Healing Rates by Month (Study 177) s = scheduled visit
Maintenance of Healing Rates by Month (Study 178) s = scheduled visit
Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with NEXIUM compared to placebo. In both studies, the proportion of patients on NEXIUM who remained in remission and were free of heartburn and other GERD symptoms was well differen-tiated from placebo. In a third multicenter open label study of 808 patients treated for 12 months with NEXIUM 40 mg, the percentage of patients that main-tained healing of erosive esophagitis was 93.7% for six months and 89.4% for one year. Symptomatic Gastroesophageal Reflux Disease (GERD) Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 patients comparing four weeks of treatment with NEXIUM 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms. Patients had 6-month history of heartburn episodes, no erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization. The percentage of patients that were symptom-free of heartburn was significantly higher in the NEXIUM groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4). No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg. The percent of patients symptom-free of heartburn by day are shown in the figures below:
Percent of Patients Symptom-Free of Heartburn by Day (Study 225) Percent of Patients Symptom-Free of Heartburn by Day (Study 226)
In three European symptomatic GERD trials, NEXIUM 20 mg and 40 mg and omeprazole 20 mg were evaluated. No significant treatment
related differences were seen.
Helicobacter pylori (H. pylori) Eradication in Patients with Duodenal Ulcer Disease Triple Therapy (NEXIUM/ amoxicillin/ clarithromycin): Two multicenter, randomized, double-blind studies were conducted using a 10 day treatment regimen. The first study (191) compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193) compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily. H. pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest ® , histology and/ or culture, at 4 weeks post-therapy were significantly higher in the NEXIUM plus amoxicillin and clarithromycin group than in the NEXIUM plus clarithromycin or NEXIUM alone group. The results are shown in the following table: H. pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen
% of Patients Cured [95% Confidence Interval]
(Number of patients)
Study Treatment Group Per-Protocol * Intent-to-Treat *
191 NEXIUMplus 84%* 77%* amoxicillin and [78, 89] [71, 82] clarithromycin (n= 196) (n= 233)
NEXIUM plus 55% 52% clarithromycin [48, 62] [45, 59] (n= 187) (n= 215)
193 NEXIUM plus 85%** 78%** amoxicillin and [74, 93] [67, 87] clarithromycin (n= 67) (n= 74)
NEXIUM 5% 4% [0, 23] [0, 21] (n= 22) (n= 24) *
Patients were included in the analysis if they had H. pylori infection docu-mented at baseline, had at least one endoscopically verified duodenal ulcer
0.5 cm in diameter at baseline or had a documented history of duodenal ulcer disease within the past 5 years, and were not protocol violators. Patients who dropped out of the study due to an adverse event related to the study drug were included in the analysis as not H. pylori eradicated.
* Patients were included in the analysis if they had documented H. pylori infection at baseline, had at least one documented duodenal ulcer at base-line, or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts were included as not H. pylori eradicated.
*p <0.05 compared to NEXIUM plus clarithromycin ** p <0.05 compared to NEXIUM alone Nexium ® (esomeprazole magnesium) Delayed-Release Capsules Nexium ® (esomeprazole magnesium) Delayed-Release Capsules Nexium ® (esomeprazole magnesium) Delayed-Release Capsules
0 1 2 3 4 5 6
Month
0 10
20
30
40
50
60
70
80
90
100 NEXIUM 40 mg (n= 92)
NEXIUM 20 mg (n= 98)
NEXIUM 10 mg (n= 91)
Placebo (n= 94) Percent
Maintained S S S NEXIUM 40 mg (n= 82)
NEXIUM 20 mg (n= 82)
NEXIUM 10 mg (n= 77)
Placebo (n= 77) 0 2 3 4 5 Month 0
10
20
30
40
50
60
70
80
90
100 S
Percent
Maintained 1S 6S 0 7 14 21 28 Diary Day 0
25
50
75
100
NEXIUM 40 mg NEXIUM 20 mg Placebo Percent of Patients Symptom-Free 0 7 14 21 28 Diary Day 0
25
50
75
100 Percent of Patients Symptom-Free NEXIUM 40 mg NEXIUM 20 mg
Placebo 2
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The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the NEXIUM plus amoxicillin and clarithromycin group was 75% (n= 156) and 57% (n= 60) respectively, in the 191 and 193 studies (per-protocol analysis). INDICATIONS AND USAGE Treatment of Gastroesophageal Reflux Disease (GERD)
Healing of Erosive Esophagitis NEXIUM is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after 4Ð 8 weeks of treatment, an additional 4Ð 8-week course of NEXIUM may be considered. Maintenance of Healing of Erosive Esophagitis NEXIUM is indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months. Symptomatic Gastroesophageal Reflux Disease NEXIUM is indicated for treatment of heartburn and other symptoms associated with GERD. H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): NEXIUM, in combination with amoxicillin and clarithromycin, is indi-cated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See Clinical Studies and DOSAGE AND ADMINISTRATION.)
In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. (See CLINICAL PHARMACOLOGY, Microbiology and the clarithromycin package insert, CLINICAL PHARMACOLOGY, Microbiology.) Page: << Prev | 1 | 2 | 3 | 4 | 5
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