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a No inferential statistics conducted for this parameter.
* (p< 0.001 versus placebo) b Gastric pH was measured every hour over a 24-hour period. Effects on Esophageal Acid Exposure In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, ACIPHEX® 20 mg and 40 mg per day decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that esophageal pH< 4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively. Text Continues Below
Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH> 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving ACIPHEX® 20 mg and in 100% of subjects receiving ACIPHEX® 40 mg. With ACIPHEX® 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment. Effects on Serum Gastrin In patients given daily doses of ACIPHEX® for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease the median fasting gastrin level increased in a dose-related manner. The group median values stayed within the normal range. In a group of subjects treated daily with ACIPHEX® 20 mg for 4 weeks a doubling of mean serum gastrin concentrations were observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. In a study of CYP2C19 genotyped subjects in Japan, poor metabolizers developed statistically significantly higher serum gastrin concentrations than extensive metabolizers. Effects on Enterochromaffin-like (ECL) Cells Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females (see Carcinogenesis, Mutagenesis, Impairment of Fertility). In over 400 patients treated with ACIPHEX® (10 or 20 mg/ day) for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton-pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats. Endocrine Effects Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with ACIPHEX® for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 . -estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6 . -hydroxycortisol, serum testosterone and circadian cortisol profile. Other Effects In humans treated with ACIPHEX® for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with ACIPHEX® and ocular effects. Microbiology Rabeprazole sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the CLINICAL STUDIES and INDICATIONS AND USAGE sections. Helicobacter pylori Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology 1 , and minimum inhibitory concentrations (MICs) were determined. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria: Clarithromycin MIC ( µ g/ mL) a Interpretation . 0.25
0.5 . 1.0 Susceptible (S) Intermediate (I) Resistant (R) Amoxicillin MIC ( µ g/ 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 using alternative
methods. b There were not enough organisms with MICs > 0.25 µ g/ mL to determine a resistance breakpoint. Standardized susceptibility test procedures require the use of laboratory 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 ( µ g/ mL) a H. pylori ATCC 43504 Clarithromycin 0.015 – 0.12 µ g/ mL
H. pylori ATCC 43504 Amoxicillin 0.015 – 0.12 µ g/ 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. Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates
Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC . 1 µ g/ mL) to H. pylori was 9% (51/ 560) at baseline in all treatment groups combined. A total of > 99% (558/ 560) of patients had H. pylori isolates which were considered to be susceptible (MIC . 0.25 µ g/ mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 µ g/ mL. Clarithromycin Susceptibility Test Results and Clinical/ Bacteriologic Outcomes: For the U. S. multicenter study, the baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results post-treatment are shown in the table below: Clarithromycin Susceptibility Test Results and Clinical/ Bacteriologic Outcomes a for a Three Drug Regimen (Rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily for 7 or 10 days)
H. pylori Positive (Persistent) Post-Treatment Susceptibility Results Days of RAC
Therapy
Clarithromycin Pretreatment Results Total Number H. pylori Negative
(Eradicated) S b I b R b No MIC 7 Susceptible b 129 103 2 0 1 23
7 Intermediate b 0 0 0 0 0 0 7 Resistant b 16 5 2 1 4 4
10 Susceptible b 133 111 3 1 2 16 10 Intermediate b 0 0 0 0 0 0
10 Resistant b 9 1 0 0 5 3 a
Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results. b
Susceptible (S) MIC . 0.25 µ g/ mL, Intermediate (I) MIC = 0.5 µ g/ mL, Resistant (R) MIC . 1 µ g/ mL Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. Amoxicillin Susceptibility Test Results and Clinical/ Bacteriological Outcomes: In the U. S. multicenter study, a total of >99% (558/ 560) of patients had H. pylori isolates which were considered to be susceptible (MIC . 0.25 µ g/ mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 µ g/ mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7-and 10-day treatment groups 75% (107/ 145) and 79% (112/ 142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs ( . 0.25 µ g/ mL) were eradicated of H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy. CLINICAL STUDIES Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)
In a U. S., multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg or 40 mg ACIPHEX® QD. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows: Aciphex PI rev-11 ver-1 revised August 2003
Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)
Percentage of Patients Healed Week
10 mg ACIPHEX® QD
N= 27
20 mg ACIPHEX® QD
N= 25
40 mg ACIPHEX® QD
N= 26 Placebo N= 25 4 63%* 56%* 54%* 0%
8 93%* 84%* 85%* 12%
*( p< 0.001 versus placebo) In addition, there was a statistically significant difference in favor of the ACIPHEX® 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p . 0.026). All ACIPHEX® groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p . 0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all ACIPHEX® groups when compared to placebo at both Weeks 4 and 8 (p . 0.007).
In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, ACIPHEX® was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment (see table below): Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed Week ACIPHEX® 20 mg QD N= 167 Ranitidine 150 mg QID N= 169 4 59%* 36%
8 87%* 66%
*( p< 0.001 versus ranitidine) ACIPHEX® 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p< 0.001). ACIPHEX® 20 mg once daily was also more effective in complete resolution of daytime heartburn (p . 0.025), and night time heartburn (p . 0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study. Long-term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance) The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric anti-secretory therapy was assessed in two U. S., multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of ACIPHEX® QD or placebo. As demonstrated in the tables below, ACIPHEX® was significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks: Long-term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance)
Percent of Patients in Endoscopic Remission
ACIPHEX® 10 mg ACIPHEX® 20 mg Placebo
Study 1 N= 66 N= 67 N= 70
Week 4 83%* 96%* 44%
Week 13 79%* 93%* 39%
Week 26 77%* 93%* 31%
Week 39 76%* 91%* 30%
Week 52 73%* 90%* 29%
Study 2 N= 93 N= 93 N= 99
Week 4 89%* 94%* 40%
Week 13 86%* 91%* 33%
Week 26 85%* 89%* 30%
Week 39 84%* 88%* 29%
Week 52 77%* 86%* 29%
COMBINED STUDIES N= 159 N= 160 N= 169
Week 4 87%* 94%* 42%
Week 13 83%* 92%* 36%
Week 26 82%* 91%* 31%
Week 39 81%* 89%* 30%
Week 52 75%* 87%* 29%
*( p< 0.001 versus placebo)
Long-term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance):
Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime Heartburn Severity at Week 52 ACIPHEX® 10 mg ACIPHEX® 20 mg Placebo
Heartburn Frequency
Study 1 46/ 55 (84%)* 48/ 52 (92%)* 17/ 45 (38%)
Study 2 50/ 72 (69%)* 57/ 72 (79%)* 22/ 79 (28%) Daytime Heartburn Severity
Study 1 61/ 64 (95%)* 60/ 62 (97%)* 42/ 61 (69%)
Study 2 73/ 84 (87%) * 82/ 87 (94%)* 67/ 90 (74%) Nighttime Heartburn Severity
Study 1 57/ 61 (93%)* 60/ 61 (98%)* 37/ 56 (66%)
Study 2 67/ 80 (84%) 79/ 87 (91%) * 64/ 87 (74%) * p . 0.001 versus placebo * 0.001< p< 0.05 versus placebo Symptomatic Gastroesophageal Reflux Disease (GERD) Two U. S., multicenter, double-blind, placebo controlled studies were conducted in 316 patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions. The percentage of heartburn free daytime and/ or nighttime periods was greater with ACIPHEX® 20 mg compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for ACIPHEX® 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 1 to 4. Figure 1: Mean Daytime heartburn scores RAB -USA -2 Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe. STUDY DAY
MEAN
SCORE -14 -7 0 7 14 21 28
0
1
2
3
4 PLACEBO, n = 68
RAB 10mg, n = 64 RAB 20mg, n = 67
Figure 2: Mean Nighttime heartburn scores RAB -USA -2
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe. STUDY DAY
MEAN
SCORE -14 -7 0 7 14 21 28
0
1
2
3
4 PLACEBO, n = 68
RAB 10mg, n = 64 RAB 20mg, n = 67
Aciphex PI rev-11 ver-1 revised August 2003 Page 9 of 17
Figure 3: Mean Daytime heartburn scores RAB -USA -3
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe. STUDY DAY
MEAN
SCORE -14 -7 0 7 14 21 28
0
1
2
3
4 PLACEBO, n = 58
RAB 20mg, n = 59
Figure 4: Mean Nighttime heartburn scores RAB -USA -3
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe. STUDY DAY
MEAN
SCORE -14 -7 0 7 14 21 28
0 1
2
3
4 PLACEBO, n = 58
RAB 20mg, n = 59 ACIPHEX® 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p< 0.001).
Healing of Duodenal Ulcers In a U. S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of ACIPHEX® QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. ACIPHEX® was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below: Healing of Duodenal Ulcers Percentage of Patients Healed
Week ACIPHEX® 20 mg QD N= 34 ACIPHEX® 40 mg QD N= 33 Placebo N= 33 2 44% 42% 21%
4 79%* 91%* 39%
* p . 0.001 versus placebo At Weeks 2 and 4, significantly more patients in the ACIPHEX® 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p . 0.018), daytime pain severity (p . 0.023), and nighttime pain severity (p . 0.035) compared with placebo patients. The only exception was the ACIPHEX® 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p= 0.094). Significant differences in resolution of daytime and nighttime pain were noted in both ACIPHEX® groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both ACIPHEX® groups compared to placebo at Weeks 2 and 4 (p< 0.001). An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg ACIPHEX® QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between ACIPHEX® and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, ACIPHEX® was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below: Healing of Duodenal Ulcers Percentage of Patients Healed Week
ACIPHEX® 20 mg QD
N= 102
Omeprazole 20 mg QD
N= 103
95% Confidence Interval for the Treatment Difference
(ACIPHEX® -Omeprazole) 2 69% 61% (– 6%, 22%)
4 98% 93% (– 3%, 15%) ACIPHEX® and omeprazole were comparable in providing complete resolution of symptoms. Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease The U. S. multicenter study was a double blind, parallel group comparison of rabeprazole, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1: 1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13 C-UBT for H. pylori . 6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens. Helicobacter pylori Eradication at . 6 Weeks After The End of Treatment
Treatment Group Percent (%) of Patients Cured (Number of Patients)
Difference (RAC – OAC)
[95% Confidence Interval] 7-day RAC* 10-day OAC Per Protocol a 84.3% (N= 166) 81.6% (N= 179) 2.8 [-5.2, 10.7]
Intent-to-Treat b 77.3% (N= 194) 73.3% (N= 206) 4.0 [-4.4, 12.5]
10-day RAC* 10-day OAC Per Protocol a 86.0%
(N= 171) 81.6% (N= 179) 4.4 [-3.3, 12.1] Intent-to-Treat b 78.1%
(N= 196) 73.3% (N= 206) 4.8 [-3.6, 13.2] 3-day RAC 10-day OAC
Per Protocol a 29.9% (N= 167) 81.6% (N= 179) -51.6 [-60.6, -42.6]
Intent-to-Treat b 27.3% (N= 187) 73.3% (N= 206) -46.0 [-54.8, -37.2] a Patients were included in the analysis if they had H. pylori infection documented at baseline, defined as a positive 13 C-UBT plus rapid urease test or culture 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 evaluable analysis as failures of therapy. b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and took at least one dose of study medication. All dropouts were included as failures of therapy. * The 95% confidence intervals for the difference in eradication rates for 7-day RAC minus 10-day RAC are (-9.3, 6.0) in the PP population and (-9.0, 7.5) in the ITT population. Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with ACIPHEX® at doses from 20 to 120 mg for up to 12 months. ACIPHEX® produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. ACIPHEX® also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of ACIPHEX® used to treat this small cohort of patients with gastric hypersecretion were well tolerated.
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