"The U.S. Food and Drug Administration today approved the first generic versions of Aciphex (rabeprazole sodium) delayed-release tablets, used to treat gastroesophageal reflux disease (GERD) in adults and adolescents (ages 12 and up).
Mechanism Of Action
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.
In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.
The antisecretory effect begins within one hour after oral administration of 20 mg ACIPHEX. The median inhibitory effect of ACIPHEX on 24-hour gastric acidity is 88% of maximal after the first dose. ACIPHEX 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH > 3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H+, K+ATPase.
TABLE 3 : GASTRIC ACID
PARAMETERS ACIPHEX VERSUS PLACEBO AFTER 7 DAYS OF ONCE DAILY DOSING
|Parameter||ACIPHEX (20 mg QD)||Placebo|
|Basal Acid Output (mmol/hr)||0.4*||2.8|
|Stimulated Acid Output (mmol/hr)||0.6*||13.3|
|% Time Gastric pH > 3||65*||10|
|*(p < 0.01 versus placebo)|
Compared to placebo, ACIPHEX, 10 mg, 20 mg, and 40 mg, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.
TABLE 4 : AUC ACIDITY (MMOL•HR/L) ACIPHEX VERSUS PLACEBO ON DAY 7 OF ONCE DAILY DOSING (MEAN ± SD)
|AUC interval (hrs)||Treatment|
|10 mg RBP
|20 mg RBP
|40 mg RBP
|08:00 -13:00||19.6 ± 21.5*||12.9 ± 23*||7.6 ± 14.7*||91.1 ± 39.7|
|13:00 -19:00||5.6 ± 9.7*||8.3 ± 29.8*||1.3 ± 5.2*||95.5 ± 48.7|
|19:00 -22:00||0.1 ± 0.1*||0.1 ± 0.06*||0.0 ± 0.02*||11.9 ± 12.5|
|22:00 -08:00||129.2 ± 84*||109.6 ± 67.2*||76.9 ± 58.4*||479.9 ± 165|
|AUC 0-24 hours||155.5 ± 90.6*||130.9 ± 81*||85.8 ± 64.3*||678.5 ± 216|
|*(p < 0.001 versus placebo)|
After administration of 20 mg ACIPHEX Tablets once daily for eight days, the mean percent of time that gastric pH > 3 or gastric pH > 4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg ACIPHEX Tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:
TABLE 5 : GASTRIC ACID
PARAMETERS ACIPHEX ONCE DAILY DOSING VERSUS PLACEBO ON DAY 1 AND DAY 8
|Parameter||ACIPHEX 20 mg QD||Placebo|
|Day 1||Day 8||Day 1||Day 8|
|Mean AUC0.24 Acidity||340.8*||176.9*||925.5||862.4|
|Median trough pH (23-hr)a||3.77||3.51||1.27||1.38|
|% Time Gastric pH > 3b||54.6*||68.7*||19.1||21.7|
|% Time Gastric pH > 4b||44.1*||60.3*||7.6||11.0|
|aNo inferential statistics conducted for this parameter.
*(p < 0.001 versus placebo)
bGastric 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 tablets 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. 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 tablets for 4 weeks, a doubling of mean serum gastrin concentrations was 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 Nonclinical Toxicology].
In over 400 patients treated with ACIPHEX Tablets (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.
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 τ-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 6τ-hydroxycortisol, serum testosterone and circadian cortisol profile.
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.
The following in vitro data are available but the clinical significance is unknown.
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 (14) and Indications and Usage (1) sections.
Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology,1 and minimum inhibitory concentrations (MICs) were determined.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates
Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 μg/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 μg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL.
For susceptibility testing information about Helicobacter Pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.
TABLE 6 : CLARITHROMYCIN
SUSCEPTIBILITY TEST RESULTS AND CLINICAL/BACTERIOLOGIC OUTCOMESa 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)
|Days of RAC Therapy||Clarithromycin Pretreatment Results||Total Number||H. pylori Negative (Eradicated)||H. pylori Positive (Persistent) Post-Treatment Susceptibility Results|
|aIncludes only patients with pretreatment and post-treatment
clarithromycin susceptibility test results.
bSusceptible (S) MIC ≤ 0.25 μg/mL, Intermediate (I) MIC = 0.5 μg/mL, Resistant (R) MIC ≥ 1 μg/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 μg/mL) to amoxicillin at baseline. The other two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/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 μg/mL) were eradicated of H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy.
ACIPHEX Delayed-Release Tablets and Delayed-Release granules in the capsule formulation are enteric-coated to allow rabeprazole sodium, which is acid labile, to pass through the stomach relatively intact.
After oral administration of 20 mg ACIPHEX tablet, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2.0 to 5.0 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing.
Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When ACIPHEX Tablets are administered with a high fat meal, Tmax is variable, which concomitant food intake may delay the absorption up to 4 hours or longer. However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus ACIPHEX Tablets may be taken without regard to timing of meals.
After oral administration to healthy adults of 10 mg ACIPHEX granules sprinkled on applesauce under fasting condition, median time (Tmax) to peak plasma concentrations (Cmax) of rabeprazole was 2.5 hours and ranged 1.0 to 6.5 hours. The plasma half-life of rabeprazole ranges from 1 to 2 hours.
In healthy adults, a concomitant high fat meal delayed the absorption of rabeprazole from ACIPHEX granules sprinkled on one Tablespoon of applesauce resulting in the median Tmax of 4.5 hours and decreased the Cmax and AUClast on average by 55% and 33%, respectively. ACIPHEX granules should be taken before a meal.
When 10 mg ACIPHEX granules administered under fasting conditions to healthy adults on one Tablespoon (15 mL) of applesauce, one Tablespoon (15mL) of yogurt, or when mixed with a small amount (5 mL) of liquid infant formula, the type of soft food did not significantly affect Tmax, Cmax, and AUC of rabeprazole.
Rabeprazole is 96.3% bound to human plasma proteins.
Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.
Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid, its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.
In 20 healthy elderly subjects administered 20 mg rabeprazole tablet once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration [see Use in Specific Population].
The pharmacokinetics of rabeprazole was studied in pediatric patients with GERD aged up to 16 years in four separate clinical studies.
Patients 12 to 16 Years of Age
The pharmacokinetics of rabeprazole was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received rabeprazole 20 mg tablets once daily for five or seven days. An approximate 40% increase in exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult volunteers.
Patients 1 to 11 Years of Age
In patients with GERD 1 to 11 years of age, following once daily administration of rabeprazole granules at doses from 0.14 to 1 mg/kg, the median time to peak plasma concentration ranged 2-4 hours and the half-life was about 2.5 hour. No appreciable accumulation was noted following 5 days of dosing compared to exposure after a single dose.
Based on population pharmacokinetic analysis, over the body weight range from 7 to 77.3 kg, the apparent rabeprazole clearance increased from 8.0 to 13.5 L/hr, an increase of 68.8%.
The mean estimated total exposure, i.e., AUC after a 10 mg dose of ACIPHEX Sprinkle in patients with GERD 1 to 11 years of age, is comparable to a 10 mg dose of ACIPHEX Tablets in adolescents and adults.
Patients < 1 Year Old
See section Pediatric Use.
Gender and Race: In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC0-∞ values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.
Renal Disease: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤ 5 mL/min/1.73 m²), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers [see DOSAGE AND ADMINISTRATION].
Hepatic Disease: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC0-24 was approximately doubled, the elimination half-life was 2-to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.
In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age-and gender-matched subjects. These increases were not statistically significant.
No information exists on rabeprazole disposition in patients with severe hepatic impairment. Please refer to the Dosage and Administration (2.9) for information on dosage adjustment in patients with hepatic impairment.
Combined Administration with Antimicrobials: Sixteen healthy volunteers genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg rabeprazole sodium, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and Cmax for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the rabeprazole AUC and Cmax increased by 11% and 34%, respectively, following combined administration. The AUC and Cmax for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns.
Concomitant Use with Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects, including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with ACIPHEX 20 mg (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7% to 95.5%) when ACIPHEX was coadministered compared to administration of clopidogrel with placebo.
Animal Toxicology And/Or Pharmacology
Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25, or 150 mg/kg/day and dogs were dosed at 3, 10, or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.
When juvenile animals were treated for 28 days with a different PPI at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed.
Healing Of Erosive Or Ulcerative GERD In Adults
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:
TABLE 7 : HEALING OF EROSIVE OR ULCERATIVE
GASTROESOPHAGEAL REFLUX DISEASE (GERD) PERCENTAGE OF PATIENTS HEALED
|Week||10 mg ACIPHEX QD
|20 mg ACIPHEX QD
|40 mg ACIPHEX QD
|*(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):
TABLE 8 : HEALING OF EROSIVE
OR ULCERATIVE GASTROESOPHAGEAL REFLUX DISEASE (GERD) PERCENTAGE OF PATIENTS
|Week||ACIPHEX 20 mg QD
|Ranitidine 150 mg QID
|*(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 nighttime 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 GERD In Adults
The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory 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:
TABLE 9 : PERCENT OF
PATIENTS IN ENDOSCOPIC REMISSION
|ACIPHEX 10 mg||ACIPHEX 20 mg||Placebo|
|*(p < 0.001 versus placebo)|
TABLE 10: PERCENT OF
PATIENTS WITHOUT RELAPSE IN HEARTBURN FREQUENCY AND DAYTIME AND NIGHTTIME
HEARTBURN SEVERITY AT WEEK 52
|ACIPHEX 10 mg||ACIPHEX 20 mg||Placebo|
|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
Treatment Of Symptomatic GERD In Adults
Two U.S. multicenter, double-blind, placebo-controlled studies were conducted in 316 adult 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 2 to 5.
FIGURE 2: MEAN DAYTIME
HEARTBURN SCORES RAB-USA-2
FIGURE 3: MEAN NIGHTTIME
HEARTBURN SCORES RAB-USA-2
FIGURE 4: MEAN DAYTIME
HEARTBURN SCORES RAB-USA-3
FIGURE 5: MEAN NIGHTTIME
HEARTBURN SCORES RAB-USA-3
In addition, the combined analysis of these two studies showed ACIPHEX 20 mg significantly improved other GERD-associated symptoms (regurgitation, belching, and early satiety) by week 4 compared with placebo (all p values < 0.005).
ACIPHEX 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p < 0.001).
Healing Of Duodenal Ulcers In Adults
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:
TABLE 11 : HEALING OF
DUODENAL ULCERS PERCENTAGE OF PATIENTS HEALED
|Week||ACIPHEX 20 mg QD
|ACIPHEX 40 mg QD
|* 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:
TABLE 12 : HEALING OF
DUODENAL ULCERS PERCENTAGE OF PATIENTS HEALED
|Week||ACIPHEX 20 mg QD
Omeprazole 20 mg QD
|95% Confidence Interval for the Treatment Difference (ACIPHEX -Omeprazole)|
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 In Adults
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 13C-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.
TABLE 13: 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 Protocola||84.3% (N=166)||81.6% (N=179)||2.8 [-5.2, 10.7]|
|Intent-to- Treatb||77.3% (N=194)||73.3% (N=206)||4.0 [-4.4, 12.5]|
|10-day 10-day RAC* OAC|
|Per Protocola||86.0% (N=171)||81.6% (N=179)||4.4 [-3.3, 12.1]|
|Intent-to- Treatb||78.1% (N=196)||73.3% (N=206)||4.8 [-3.6, 13.2]|
|3-day RAC||10-day OAC|
|Per Protocola||29.9% (N=167)||81.6% (N=179)||- 51.6 [- 60.6, - 42.6]|
|Intent-to- Treatb||27.3% (N=187)||73.3% (N=206)||-46.0 [- 54.8, - 37.2]|
|aPatients were included in the analysis if they had H.
pylori infection documented at baseline, defined as a positive 13C-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.
bPatients 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 In Adults
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.
Symptomatic GERD in Adolescents 12 to 16 Years of Age
In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or suspected or endoscopically proven GERD were randomized and treated with either ACIPHEX 10 mg or ACIPHEX 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy.
GERD in Pediatric Patients 1 to 11 Years of Age
The use of ACIPHEX Sprinkle in pediatric patients 1 to 11 years of age is supported by a two-part, multicenter, randomized, double-blind, parallel 2 dose arms clinical trial which was conducted in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment.
Part 1 was 12 weeks in duration. Patients were randomized to one of two rabeprazole dose levels based on body weight. Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg rabeprazole, and those with body weight ≥ 15 kg received either 10 or 20 mg of rabeprazole. Part 2 was a 24-week double-blinded extension of Part 1 (on same dose assigned in Part 1). Endoscopic evaluations were performed at 12 weeks (Part 1) and 36 weeks (Part 2) to assess esophageal healing. No prespecified formal hypothesis testing was conducted.
For Part 1, rates of endoscopic healing were calculated and are shown in Table 14.
TABLE 14 : SHORT-TERM
(12-WEEK) HEALING RATES IN 1-to 11-YEAR-OLD CHILDREN (PART 1)
|Endoscopic Classification of GERD At Baseline||Healing Rate at 12 weeks|
|Body Weight < 15 kg||Body Weight ≥ 15 kg|
|5 mg dose||10 mg dose||10 mg dose|
|Erosivea||88% (7/8)||83% (5/6)||71% (12/17)|
|Non-erosiveb||78% (7/9)||100% (10/10)||81% (17/21)|
|aHetzel-Dent score ≥ 2
bHetzel-Dent score = 1
Of the 87 patients with healing in Part 1, 64 patients were enrolled into Part 2. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. Of the 52 patients with available data, healing was observed in 47 (90%) patients at 36 weeks.
1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.
Last reviewed on RxList: 1/9/2015
This monograph has been modified to include the generic and brand name in many instances.
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