Download This reprint contains information which is not found in the FDA

This reprint contains information which is not found in the FDA-approved Full Prescribing
Information (PI) for ACIPHEX® Sprinkle™(rabeprazole sodium) Delayed-Release Capsules. The
information provided in this reprint is intended for information only. FSC Pediatrics, Inc. does
not recommend the use of AcipHex Sprinkle in any manner that is not consistent with, or is
outside the scope of, the PI. Please read the full indication and Important Safety Information
for AcipHex Sprinkle provided below.
Indication for use:
In pediatric patients, 1 – 11 years of age, ACIPHEX® Sprinkle™ is indicated for treatment of
GERD for up to 12 weeks.
Important Safety Information about ACIPHEX® Sprinkle™(rabeprazole sodium) DelayedRelease Capsules:
Contraindications:
ACIPHEX® Sprinkle ™ is contraindicated in patients with known hypersensitivity to rabeprazole,
substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions
may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial
nephritis, and urticaria.
Warnings and Precautions:
o Symptomatic response to therapy does not preclude the presence of gastric malignancy
o
As with all PPIs, patients treated concomitantly with warfarin may need to be monitored
for increases in INR and prothrombin time. Increases in INR and prothrombin time may
lead to abnormal bleeding and even death
o
Acute interstitial nephritis has been observed in patients taking PPIs. Discontinue ACIPHEX
if acute interstitial nephritis develops
o
Daily long-term use may lead to malabsorption or deficiency of vitamin B-12
o
PPI therapy may be associated with an increased risk of C. difficile associated diarrhea,
especially in hospitalized patients
o
Long-term and multiple daily dose PPI therapy may be associated with an increased risk for
osteoporosis-related fractures of the hip, wrist or spine
o
Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. Serious
adverse events include tetany, arrhythmias, and seizures. Consider monitoring magnesium
levels in patients on prolonged PPI therapy or concomitant medications such as digoxin or
medications that may cause hypomagnesemia (e.g., diuretics)
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o
Concomitant use of PPIs with high dose methotrexate may elevate and prolong
methotrexate serum levels or its metabolite. Withdrawal of PPI may be considered in some
patients.
Adverse Events:
o In children (1-11 years of age) adverse reactions that occurred in ≥5% of patients included
abdominal pain, diarrhea and headache.
Drug Interactions:
o ACIPHEX® Sprinkle™ inhibits gastric acid secretion and may interfere with the absorption of
drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole,
iron salts, and digoxin)
o
ACIPHEX® Sprinkle™ may reduce the plasma levels of atazanavir
o
Rabeprazole has been shown to inhibit cyclosporine metabolism in vitro
o
ACIPHEX® Sprinkle™ may increase serum levels of methotrexate
For more information, please refer to the accompanying AcipHex® Sprinkle™ Full Prescribing
Information.
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value, such as reprints, provided to certain healthcare professionals. If you have questions
regarding this disclosure, please contact us at 1-866-764-7822 for more information.
ACPX0278 Rev 1 January 2015
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Reprinted from Journal of Pediatric Gastroenterology Nutrition
Vol. 57 No. 6 December 2013
Copyright © 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
Published by Lippincott Williams & Wilkins Printed in U.S.A.
ORIGINAL ARTICLE: GASTROENTEROLOGY
Efficacy and Safety of Rabeprazole in Children
(1–11 Years) With Gastroesophageal Reflux Disease
�
Ibrahim Haddad, yJaroslaw Kierkus, zEduardo Tron, §April Ulmer, jjPeter Hu,
jj
Sheldon Sloan, jjSteven Silber, and jjGerhard Leitz
ABSTRACT
Objective: Evaluate the efficacy and safety of rabeprazole in children, 1 to
11 years old, with endoscopically/histologically proven gastroesophageal
reflux disease (GERD).
Methods: Children were randomized to 0.5- or 1.0-mg/kg rabeprazole
granule formulation for 12 weeks. The dose was further determined by
weight: children 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and
children �15 kg (high-weight cohort) received 10 or 20 mg. The primary
endpoint was endoscopic/histologic healing at week 12 (defined as grade
0 on the Hetzel-Dent classification scale and/or grade 0 on the Histological
Features of Reflux Esophagitis scale).
Results: Overall, 81% (87/108) achieved endoscopic/histologic healing at
week 12 with higher healing in the low-weight cohort (82% [5-mg dose],
94% [10-mg dose]) compared with high-weight cohort (76% [10-mg dose],
78% [20-mg dose]). There was a significant (P < 0.001) decrease in the
mean Total GERD Symptoms and Severity score from 19.7 points (baseline)
to 8.6 points (week 12), with 26% fewer children reporting GERD symptoms
at week 12. The average frequency of symptoms per child decreased from
7.7 (week 1) to 4.7 (week 12). The GERD Symptom Relief score showed that
71% of children felt better, 81% were rated ‘‘good to excellent’’ on the
Global Treatment Satisfaction scale by the investigator; 77% were rated
‘‘good to excellent’’ on the Clinical Global Impressions-Improvement scale
by the parent/caregiver. The most common (>10%) treatment-emergent
adverse events included cough and vomiting (14% each), abdominal pain
(12%), and diarrhea (11%).
Conclusions: Rabeprazole was effective and safe in 1- to 11-year-old
children with GERD.
Key Words: gastroesophageal reflux disease, pediatric, rabeprazole
Received January 15, 2013; accepted July 11, 2013.
From �Pediatric & Adolescent Gastroenterology & Nutrition, Youngstown,
OH, the yChildren’s Memorial Health Institute, Warsaw, Poland, the
zGeisinger Medical Center Clinic, Wilkes Barre, PA, §Gastrointestinal
Associates, Jackson, MS, and jjJanssen Research & Development, LLC,
Titusville, NJ.
Address correspondence and reprint requests to Ibrahim Haddad, MD,
Pediatric & Adolescent Gastroenterology & Nutrition, 8560 South
Avenue #3, Youngstown, OH 44514 (e-mail: [email protected]).
This study was financially supported by funding from Janssen Research &
Development, LLC (previously known as Johnson & Johnson Pharmaceutical Research & Development, LLC) and Eisai Medical Research,
Inc. The sponsors also provided a formal review of this manuscript.
www.clinicaltrials.gov registration number: NCT00787891.
The study results were presented at Digestive Disease Week, May 7–10,
2011, Chicago, IL.
G.L., P.H., S. Sloan, and S. Silber are employees of Janssen Research &
Development, LLC. The other authors report no conflicts of interest.
Copyright # 2013 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3182a4e718
798
(JPGN 2013;57: 798–807)
G
astroesophageal reflux (GER) is a normal physiological
process experienced by almost 100% of infants that resolves
spontaneously by 1 year of age in most children (1,2). Little is
known about its prevalence in older children and adolescents
because numerous disorders can present with the same symptoms
and signs as GER or gastroesophageal reflux disease (GERD). It is
estimated that approximately 2% to 22% of children between the
ages of 3 to 18 years experience symptoms of GERD (1). The
pathophysiology of GERD in children older than 1 year is similar to
that in adults because it involves excessive transient relaxations of
the lower esophageal sphincter and ineffective esophageal peristalsis along with delayed gastric emptying and gastric distension (3);
however, the GERD symptoms seen in children and adolescents are
distinctly different from classic heartburn seen in adults (1). Typical
GERD symptoms in children include recurrent regurgitation with or
without vomiting, swallowing difficulties that lead to weight loss or
failure to thrive, respiratory problems (wheezing, asthma, or recurrent pneumonia), abdominal pain, irritability, and sleeping problems (4–6). These symptoms, if not treated in time, may lead to
complications and can severely affect the quality of life of these
children and their families (7). There is increasing evidence that
GERD is a lifelong condition in some individuals, and development
of GERD during childhood increases the risk of GERD and its
complications during adulthood (1). Early detection and treatment
of GERD in childhood may result in better disease outcomes and
improved quality of life in adults (1).
Proton pump inhibitors (PPIs) have proven safe and effective
for GERD treatment in adult and adolescent populations (8).
Several PPIs have also been approved for the treatment of children
1 year or older based on studies showing the healing of esophagitis
in 1- to 11-year-olds (9–12).
Rabeprazole is a PPI approved in the United States, the
European Union, and Japan, and is marketed globally as entericcoated 10-mg and 20-mg tablets; it is prescribed for the treatment of
acid-related disorders, including GERD in adults and adolescents
(13,14). On the contrary, there are presently no published, reported,
or company-sponsored studies for the use of rabeprazole in the
treatment of GERD in children younger than 12 years. Thus, the
present study was conducted to evaluate the efficacy and safety of
rabeprazole for the treatment of 1- to 11-year-old children with
GERD. Because children may find it difficult to swallow tablets, a
new rabeprazole delayed-release granule formulation was introduced in this study, which is similar in action to the enteric-coated
10- and 20-mg tablets but can be mixed with soft food before giving
it to children. The present study is by far the largest study conducted
in this population (1–11 years) and, unlike other studies with other
PPIs, it involves children with endoscopically confirmed GERD
who were reevaluated endoscopically at the conclusion of the study.
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METHODS
Study Design
This was a randomized, double-blind (DB), multicenter
study of 2 target-dose levels (0.5 and 1.0 mg/kg) of rabeprazole
granules in children 1 to 11 years old. The dosing was further
determined by the body weight: children weighing 6.0 to 14.9 kg
(low-weight cohort) received an actual dose of 5 mg (if randomized
to 0.5 mg/kg) or 10 mg (if randomized to 1.0 mg/kg), and children
weighing �15.0 kg (high-weight cohort) received an actual dose of
10 mg (if randomized to 0.5 mg/kg) or 20 mg (if randomized to
1.0 mg/kg).
The study consisted of a 21-day screening period and a
12-week DB treatment period. For evaluation of the primary endpoint
(endoscopic/histologic healing), an esophagogastroduodenoscopy
with biopsy was performed at screening and at week 12. Secondary
endpoints included assessment of the frequency, severity and relief of
GERD symptoms, and the concomitant use of antacids as rescue
medication. Investigator-assessed treatment satisfaction and parent/
caregiver-assessed overall impressions of clinical improvement were
determined at the end of the 12-week treatment period.
Efficacy and Safety of Rabeprazole in Pediatric Patients
study. The rabeprazole dose was administered as the contents of
either 2.5 mg or 5.0 mg rabeprazole sprinkle capsules with the dose
adjusted to the child’s body weight.
The selected doses are known to be therapeutically effective
and safe in adults (15) and adolescents (16), and the highest dose
used in this study did not exceed the maximum labeled adult dose
(20-mg dose). Dose selection was based on earlier studies that
demonstrated that the known target range for plasma level of
exposure (area under the curve, AUC) of rabeprazole for therapeutic
acid suppression in adults and adolescents treated with 10- and
20-mg rabeprazole was 400 to 800 ng � h�1 � L�1 (17). Pharmacokinetic modeling, derived from preliminary pharmacokinetics
studies in 1- to 11-year-old children with GERD, showed that
once-daily administration of 0.5 and 1 mg/kg rabeprazole produced
plasma AUC1 values that were comparable with those observed in
adults receiving 10 and 20 mg rabeprazole, respectively (17).
A small amount of soft food or infant formula was used as a
dosing vehicle to administer rabeprazole. Everyone, including the
investigator, the contract research organization, and in-house study
personal, was blinded in the study.
Patient Population
Efficacy and Safety Assessments
Children of both sexes, ages 1 to 11 years, who were enrolled
in this study had endoscopically proven GERD (defined as grade
�1 on the Hetzel-Dent classification scale and grade >0 on the
Histological Features of Reflux Esophagitis scale) and had a history
of at least 1 GERD symptom (heartburn, dysphagia, belching/
burping, regurgitation, vomiting, hoarseness, coughing, choking,
fullness during eating, anorexia, nausea, abdominal pain) occurring
at least 1 to 2 times daily within 3 months before screening. Girls
who had reached their menarche were required to use an effective
method of birth control.
Treatment with any PPIs or histamine type 2 receptor
antagonist (H2 blocker) medications for GERD was discontinued
at least 3 days before the start of rabeprazole treatment. Patients
who were treatment-naı̈ve could be enrolled, except at 1 site in
Israel, which included only those children who had previously
failed treatment with a PPI based on the local medical center ethics
committee recommendation.
The study excluded children with a history or endoscopic
findings of eosinophilic esophagitis; persistent milk protein allergy,
allergic gastroenteropathy, or allergies to PPIs; infection with
Helicobacter pylori; and those participating in any other investigational drug trial within 30 days before screening. The use of sucralfate, domperidone, or any medication that affects gastrointestinal (GI)
motility (caffeine, baclofen, erythromycin, and metoclopramide), as
well as digoxin, digitalis preparations, ketoconazole, and theophylline, was prohibited from 3 days before randomization and throughout the study.
The study protocol was approved by the independent ethics
committee or institutional review board, and the study was conducted
in accordance with the ethical principles originating in the Declaration of Helsinki and in accordance with the ICH Good Clinical
Practice guidelines, applicable regulatory requirements, and in compliance with the protocol. Parents or legally accepted representatives
of children provided written informed consent before participation in
the study. Assent was also obtained from the children 7 years or older
who were capable of understanding the study.
The primary endpoint was the macroscopic and histologic
healing at week 12 defined as grade 0 on the Hetzel-Dent classification scale (18), and/or grade 0 on the Histological Features of
Reflux Esophagitis scale (19). The Hetzel-Dent classification scale
defined scores of grade 0 (normal esophageal mucosa with no
abnormalities noted), grade 1 (no macroscopic erosions visible but
erythema, hyperemia, and/or friability may be present), grade 2
(superficial erosions or ulcers involving <10% of the mucosa of the
distal 5 cm of the esophagus), grade 3 (superficial erosions or ulcers
involving 10%–50% of the mucosa of the distal 5 cm of the
esophagus), and grade 4 (deep ulcers anywhere in the esophagus
or confluent erosion or ulceration of >50% of the mucosal surface
of the distal 5 cm of the esophagus). The Histological Features of
Reflux Esophagitis scale defined scores as follows: grade 0 (none),
grade 1 (basal zone hyperplasia and elongation of papillae), grade 2
(grade 1, and in growth of vessels in the papillae), grade 3 (grade 2,
and presence of 1 to 19 eosinophils and/or neutrophils on the
most involved high-power field), grade 4 (grade 3 and presence
of >20 eosinophils and/or neutrophils on the most involved highpower field), grade 5 (mucosal erosions with or without ulcerations). The endoscopy was performed locally by the gastroenterologist. The biopsy was evaluated and graded by the local
pathologist using the above criteria.
Secondary efficacy endpoints included the assessment of
frequency and severity of GERD symptoms using the Total GERD
Symptom and Severity scale (12-symptom scale measuring the
frequency and severity of heartburn, dysphagia, belching/burping,
regurgitation, vomiting, hoarseness, coughing, choking, fullness
during eating, anorexia, nausea, abdominal pain) (20). For each
symptom, the frequency (0 ¼ never; 1 ¼ 1–2 times; 2 ¼ 3–4 times;
3 ¼ 5–6 times; 4 ¼ �7) and severity (1 ¼ mild; 2 ¼ moderate;
3 ¼ severe) were assessed. For each individual symptom, the score
is defined as the sum of the frequency and severity of that symptom
(maximum attainable individual score ¼ 7). The total score is
defined as the sum of the scores of all the symptoms (maximum
attainable total score ¼ 84). Higher observed scores indicate a more
serious condition. Parents/caregivers completed a daily diary and
recorded the presence and severity of the 12 predefined GERD
symptoms and the amount of antacids being used via an electronic
handheld device. The child’s symptom relief was assessed at weeks
2, 4, 6, 8, and 12 using the Overall GERD Symptom Relief score,
Study Dose
All of the children took the study treatment daily in the
morning for the duration of the 12-week DB treatment phase of the
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graded by the parent/caregiver as 1 (better), 0 (no change), and
�1 (worse). Treatment satisfaction and impression of improvement at the end of treatment were assessed using the investigatorrated, 4-point Global Treatment Satisfaction (21) and the parent/
caregiver-rated 4-point Clinical Global Impressions-Improvement
(CGI-I) scores (both 0 ¼ poor, 1 ¼ fair, 2 ¼ good, 3 ¼ excellent)
(22). Safety assessments included the monitoring of adverse events,
clinical laboratory testing, vital signs, and physical examination.
Statistical Analysis
To determine the macroscopic and histologic healing of the
4 dose groups, the percentage of patients who were healed was
calculated for each group. A logistic regression was performed
using the 0 to 1 healing indicator (healing indicator was set to 1 if
the child had grade 0 on either of the 2 scales by week 12 [healed],
and was set to 0 if neither scale had a value of grade 0 by week
12 [not healed]) at week 12 as the dependent variable, treatment
group and age group as categorical factors, and body weight as a
covariate. The estimate of the healing rate and the 95% confidence
interval was derived for each treatment dose group. No formal
hypothesis was tested for the 12-week, DB treatment phase.
Secondary efficacy endpoints were analyzed with the
Cochran-Mantel-Haenszel test stratified by age group (1–5 years
and 6–11 years). The change in the weekly average Total GERD
Symptom score, change in the weekly average GERD Symptom
Severity score, the frequency and amount of antacid use, and the
change in the percentage of days with any GERD symptom were
summarized by dose and age group.
Efficacy analyses were conducted in the intention-to-treat
population, which included all of the randomized patients who had
at least 1 postbaseline efficacy assessment. The safety assessments
were conducted in the safety population, which included all of the
randomized patients who received at least 1 dose of study drug.
Computations for all of the results were performed using the
Statistical Analysis System version 9.2 (SAS Institute, Cary, NC).
Sample Size Determination
Following the Food and Drug Administration’s guidance
regarding this type of study (Food and Drug Administration’s
written request and recommendations from the pediatric committee
of the European Medical Evaluations Agency for the pediatric
investigational plan for the European Union), a sample size of
100 children was determined as appropriate to evaluate the efficacy
and safety of rabeprazole at target doses of 0.5 mg/kg (10 mg
maximum dose) and 1.0 mg/kg (20 mg maximum dose) in this
study. This was based on the assumption that if the healing rate was
85%, then the lower limit of the 95% confidence interval would be
74%, which was much higher than the most conservative scenario of
a spontaneous healing rate of 58% (23).
RESULTS
Study Participation
This study was conducted in 9 countries (United States,
Belgium, Denmark, France, Italy, Poland, Israel, South Africa,
and India) from January 30, 2009 to August 19, 2010. Of the
239 children screened, 127 children were randomized and 108
(85%) had at least 1 postbaseline assessment for primary endpoint
(intention-to-treat population). The majority of the children who
were screened but did not enroll into the study either did not meet
the inclusion criteria or refused to undergo endoscopic and/or
biopsy evaluations. Overall, 19 (15%) children withdrew before
800
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Volume 57, Number 6, December 2013
study completion (Fig. 1). None of the 127 children enrolled into the
study had a history of acute life-threatening events resulting from
manifestations of GERD.
The mean age of children was 5.7 years, with 54% of children
ages 1 to 5 years and 46% of children ages 6 to 11 years. Most
children (78%) were white (Table 1). All of the children in the older
age group (6–11 years) were �15 kg (high-weight cohort), whereas
42% of the children ages 1 to 5 years weighed �15 kg.
Before study entry, 29% children were receiving PPI treatment, 22% received antacids, 15% used H2-blockers, and 2% were
taking prokinetics. On average, children had 4 to 5 GERD symptoms at baseline. The most prevalent symptom was belching (69%)
followed by abdominal pain (68%), coughing (62%), fullness while
eating (56%), regurgitation (55%), nausea (42%), heartburn (41%),
hoarseness (31%), vomiting (29%), anorexia (27%), dysphagia
(23%), and choking (16%). The median duration of study drug
exposure was 84 days (range 6–119 days).
Primary Efficacy (Endoscopic/Histological
Healing)
Overall, 81% (87/108) children achieved endoscopic/histologic healing during the 12-week DB treatment period. The healing
rates were higher in the low-weight cohort (82% [5-mg dose]; 94%
[10-mg dose]) compared with those of the high-weight cohort (76%
[10-mg dose]; 78% [20-mg dose]). Nine (10%) children achieved
healing as a result of improvement in histology score while not
reaching Hetzel-Dent grade 0 (2 children each in 5-mg and 10-mg
groups of low-weight cohort, 1 child of the 10-mg high-weight
cohort and 4 in the 20-mg group).
There was a significant (P < 0.001; paired t test) decrease in
the mean (standard deviation) Hetzel-Dent score from 1.5 (0.71)
points (baseline) to 0.3 (0.63) points (week 12) for all of the
children. At baseline, 61% of 108 children had a Hetzel-Dent score
identified as grade 1, 30% had grade 2, 6% had grade 3, and 3% had
grade 4. At the end of 12 weeks, 72% of all of the children improved
to grade 0, 81% had a Hetzel-Dent score improvement of �1, 18%
had no change, and 1% experienced a Hetzel-Dent score increase
from grade 1 to grade 2. A similar proportion of children in each
dose group had a Hetzel-Dent score improvement of �1: 82%
(5 mg, low-weight cohort), 81% (10 mg, low-weight cohort), 87%
(10 mg, high-weight cohort), and 76% (20 mg, high-weight cohort)
(Table 2).
During the esophagogastroduodenoscopy, biopsies were
obtained from the duodenum, the stomach (antrum), mid-esophagus, and 2.5 cm above the gastroesophageal junction. Overall, 38%
of 108 children had a histology score of grade 1 at baseline, 15% had
grade 2, 39% had grade 3, 4% had grade 4, and 5% had grade 5.
There was a significant (P < 0.001; paired t test) decrease in the
mean (standard deviation) histology score from 2.2 (1.13) points
(baseline) to 1.4 (1.35) points (week 12) for all of the children. At
the end of the 12-week treatment period, 38% children improved to
grade 0, 57% had an improvement in the histology score �1, 28%
had no change, and 5% showed worsening (Table 2).
Secondary Efficacy
Total GERD Symptom and Severity Score
There was a significant (P < 0.001; paired t test) decrease in
the mean Total GERD Symptoms and Severity score from 19.3
points (baseline) to 8.6 points (week 12) for all of the children. The
frequency and severity of GERD symptoms decreased rapidly in all
4 dose groups until week 4. Thereafter, the score remained
unchanged until week 12 (Fig. 2). The change from baseline at
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Efficacy and Safety of Rabeprazole in Pediatric Patients
21-day screening period N = 239
Randomization N = 127
High-weight cohort
body weight ≥ 15kg
Low-weight cohort
body weight 6–14.9kg
Low dose 5 mg
N = 21
High dose 10 mg
N = 19
Withdraw n = 4 (19%)
– Adverse event n = 1 (5%)
– Lost to follow-up n = 1
(5%)
– Withdrew consent n = 2
(10%)
Withdraw n = 3 (16%)
– Adverse event n = 1 (5%)
– Withdrew consent n = 1
(5%)
– Other n = 1 (5%)
Completed n = 17 (81%)
Low dose 10 mg
N = 44
High dose 20 mg
N = 43
Withdraw n = 6 (14%)
– Lost to follow-up n = 1 (2%)
– Physicaian decision n = 1
(2%)
– Withdrew consent n = 4 (9%)
Withdraw n = 6 (14%)
– Adverse event n = 1 (2%)
– Lost to follow-up n = 2 (5%)
– Protocol violation n = 1 (2%)
– Withdrew consent n = 1 (2%)
– Other n = 1 (2%)
Completed n = 16 (84%)
Completed n = 38 (86%)
Completed n = 37 (86%)
FIGURE 1. Patient disposition.
week 12 was similar across all of the dose groups, except the 5-mg
group, which had a greater score reduction (�13.6 points) (Table 3).
During the 12-week treatment period, there was a decrease in
both the frequency and severity of GERD symptoms. Overall, 26%
fewer children reported GERD symptoms at the end of the 12-week
DB treatment period, and the average number of symptoms
decreased from 7.7 at week 1 to 4.7 at week 12. The largest
percentage improvement in the frequency and severity of individual
symptoms was reported for vomiting (86%), nausea (82%), hoarseness and choking (80% each), and dysphagia (79%) in all of the
children. In the 6- to 11-year-old age group, the best improvement
was seen for vomiting (100%) and choking (94%), whereas in the
1- to 5-year-old age group, the best improvement was noted for
hoarseness and dysphagia (92% each), followed by nausea (84%)
and vomiting (80%) (Table 4).
GERD Symptom Relief Score
The improvement in the GERD Symptom Relief score was
statistically significant (P < 0.001). The majority of children
reported symptom relief at every postbaseline visit, with 58% to
73% reporting they felt better (Fig. 3). No change in symptoms was
reported for 22% to 36% of children, and 3% to 9% felt worse. At
week 12, the GERD Symptom Relief score showed that 85 of
TABLE 1. Demographics and baseline characteristics (all randomized sets)
Rabeprazole treatment
Low-weight cohort
Parameter
Age group, n (%)
1–5 y
6–11 y
Age, y
Mean (SD)
Sex, n (%)
Male
Race, n (%)
White
Black or African American
Asian
Others
Weight, kg
Mean (SD)
BMI, kg/m2
Mean (SD)
5 mg, N ¼ 21
High-weight cohort
10 mg, N ¼ 19
10 mg, N ¼ 44
20 mg, N ¼ 43
Total, N ¼ 127
21 (100)
0
19 (100)
0
15 (34)
29 (66)
14 (33)
29 (67)
69 (54)
58 (46)
2.4 (1.2)
1.9 (1.1)
7.6 (2.9)
7.0 (2.7)
5.7 (3.4)
9 (43)
11 (58)
25 (57)
26 (60)
71 (56)
13
3
1
2
38 (86)
2 (5)
0
4 (9)
32 (74)
7 (16)
0
4 (9)
99
13
3
12
16
1
2
2
(76)
(5)
(10)
(10)
(68)
(16)
(5)
(11)
(78)
(10)
(2)
(9)
12.4 (1.9)
11.5 (2.3)
32.7 (15.2)
28.5 (11.8)
24.7 (14.3)
15.1 (2.3)
15.0 (1.6)
18.7 (4.3)
17.7 (3.3)
17.2 (3.6)
BMI ¼ body mass index; ITT ¼ intention-to-treat; SD ¼ standard deviation.
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TABLE 2. Change from baseline to week 12 in the Hetzel-Dent endoscopic classification scale scores and histological features of reflux esophagitis
scale scores during the double-blind treatment phase (ITT population)
Rabeprazole treatment
Low-weight cohort
Hetzel-Dent endoscopic classification scale scores
Baseline, mean (SD)
Wk 12, mean (SD)
Change from baseline to wk 12, n
Mean (SD)
Change in category from baseline to wk 12, n (%)
�4
�3
�2
�1
0
1
2
3
4
Histological features of Reflux Esophagitis scale scores
Baseline, mean (SD)
Wk 12, mean (SD)
Change from baseline to wk 12, n
Mean (SD)
Change in category from baseline to wk 12, n (%)
�5
�4
�3
�2
�1
0
1
2
3
4
5
High-weight cohort
5 mg, N ¼ 21
10 mg, N ¼ 19
10 mg, N ¼ 44
20 mg, N ¼ 43
Total, N ¼ 127
1.7 (0.97)
0.4 (0.8)
17
�1.4 (1.06)
1.4 (0.60)
0.3 (0.79)
16
�1.1 (0.72)
1.5 (0.70)
0.3 (0.57)
38
�1.2 (0.75)
1.4 (0.62)
0.4 (0.54)
37
�1.0 (0.85)
1.5 (0.71)
0.3 (0.63)
107
�1.2 (0.83)
1
1
4
8
3
(6)
(6)
(24)
(47)
(18)
0
0
0
0
2.1 (1.28)
1.7 (1.53)
17
�0.5 (1.37)
0
0
2 (12)
1 (6)
6 (35)
4 (24)
3 (18)
1 (6)
0
0
0
0
0
5 (31)
8 (50)
3 (19)
0
0
0
0
2.4 (1.57)
1.4 (1.36)
16
�1.1 (1.93)
1
1
2
1
5
4
(6)
(6)
(13)
(6)
(31)
(25)
0
2 (13)
0
0
0
2
10
21
5
0
(5)
(26)
(55)
(13)
0
0
0
0
2
6
20
8
1
0
(5)
(16)
(54)
(22)
(3)
0
0
0
2.3 (1.01)
1.5 (1.29)
38
�0.8 (1.17)
2.0 (0.93)
1.2 (1.34)
37
�0.7 (1.37)
0
0
4 (11)
6 (16)
12 (32)
13 (34)
2 (5)
1 (3)
0
0
0
0
0
4 (11)
6 (16)
11 (30)
9 (24)
6 (16)
0
1 (3)
0
0
1
5
25
57
19
1
(1)
(5)
(23)
(53)
(18)
(1)
0
0
0
2.2 (1.13)
1.4 (1.35)
108
�0.8 (1.39)
1
1
12
14
34
30
11
4
1
(1)
(1)
(11)
(13)
(31)
(28)
(10)
(4)
(1)
0
0
ITT ¼ intention-to-treat; SD ¼ standard deviation.
120 (71%) children felt better, 27 (23%) felt no change, and 8 (7%)
felt worse. Results were similar across age and treatment groups.
Response by Baseline Hetzel-Dent
Classification Scale Scores
Investigator-Assessed Global Treatment
Satisfaction Score and Parent/Caregiver-Rated
CGI-I Score
Overall, 42 of 108 children (39%) had erosive GERD (HetzelDent score >1), whereas 66 (61%) had nonerosive GERD (HetzelDent score 1) at baseline. A post-hoc analysis showed that at the end
of 12 weeks, the healing rates (Heztel-Dent score 0) were similar for
both erosive GERD (83%) and nonerosive GERD (79%). The change
from baseline to week 12 in the Total GERD Symptom and Severity
score was also similar between the groups with erosive GERD
(�10.2 points) and nonerosive GERD (�9.9 points). In addition,
there was no notable outcome difference with regard to antacid use,
Overall GERD Symptom Relief score, and Global Treatment Satisfaction score between children with erosive and nonerosive GERD.
At the end of the 12-week treatment period, the investigatorassessed child’s Global Treatment Satisfaction showed that 35%
scored ‘‘excellent,’’ 46% scored ‘‘good,’’ 10% scored ‘‘fair,’’ and
8% scored ‘‘poor.’’ Parent/caregiver-rated CGI-I scores showed
77% of children scored ‘‘good’’ to ‘‘excellent,’’ 14% scored
‘‘fair,’’ and 8% scored ‘‘poor’’ (Table 5).
Antacid Use
Overall, 46% of children were using antacids during week 1
and 29% during week 12. The decrease in the proportion of children
using concomitant antacids was similar across all of the groups
(14%–15%) except for the 10-mg (high-weight cohort) dose group
(28%).
802
Association Between Total GERD Symptom and
Severity Score and Change in Hetzel-Dent
Score from Baseline to Week 12
When comparing endoscopic changes (Hetzel-Dent score)
with clinical improvements (Total GERD Symptom and Severity
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Efficacy and Safety of Rabeprazole in Pediatric Patients
24
5 mg low-weight cohort (N = 21)
22
10 mg low-weight cohort (N = 19)
10 mg high-weight cohort (N = 44)
Weekly average total GERD
Symptom and severity score
20
20 mg high-weight cohort (N = 43)
18
16
14
12
10
8
6
4
2
0
Baseline 1
2
3
4
5
6
7
8
9
10
11
12
Study week
FIGURE 2. Weekly average Total GERD Symptom and Severity Score from baseline to week 12 (intention-to-treat population).
GERD ¼ gastroesophageal reflux disease.
Severity score. Children with no change or worsening of �1 grade
on the Histological Features of Reflux Esophagitis scale had an
overall mean improvement of 11.4 points on the Total GERD
Symptom and Severity score. Children with an improvement of
1 grade on the Histological Features of Reflux Esophagitis scale had
a mean improvement of 9.1 points, and those with an improvement
of �2 grades on the Histological Features of Reflux Esophagitis
scale had a mean improvement of 12.6 points on the Total GERD
Symptom and Severity score.
score) for all of the children from baseline to week 12, the following
nonstatistically significant trend was noted: children who had no
change or who worsened by �1 on the Hetzel-Dent classification
scale had a low mean improvement of 7.6 points on the Total GERD
Symptom and Severity score; children with an improvement by
1 grade on the Hetzel-Dent classification scale had a better mean
improvement of 11.1 points; children with a Hetzel-Dent score
that improved by �2 grades had the best mean improvement of
13.1 points on the Total GERD Symptom and Severity score.
Association Between Total GERD Symptom
Severity Score and Change in Histological
Features of Reflux Esophagitis Scale From
Baseline to Week 12
Safety
In total, 96 (76%) of 127 children reported at least 1 treatment-emergent adverse event (TEAE) during the 12-week DB
phase (Table 6). The most commonly (>10%) reported TEAEs
were vomiting (14%), cough (14%), abdominal pain (12%), and
diarrhea (11%). Of these, diarrhea and cough were more frequent
(21% each) in the 10-mg (low-weight cohort) dose group, whereas
There was no consistent pattern observed when comparing
changes in the Histological Features of Reflux Esophagitis scale
scores and improvements in the Total GERD Symptom and
TABLE 3. Total GERD Symptom and Severity scores (ITT population)
Rabeprazole treatment
Low-weight cohort
5 mg, N ¼ 21
Baseline mean (SD)
Wk 12, n
Wk 12, mean (SD)
Change from baseline to wk 12
Mean (SD)
10 mg, N ¼ 19
High-weight cohort
10 mg, N ¼ 44
20 mg, N ¼ 43
Total, N ¼ 127
23.2 (13.63)
18
6.7 (8.80)
16.3 (10.50)
18
6.4 (6.27)
19.1 (10.90)
43
8.4 (7.75)
18.9 (9.13)
41
10.7 (9.47)
19.3 (10.64)
120
8.6 (8.42)
�13.6 (13.07)
�9.0 (11.17)
�10.6 (11.13)
�8.3 (9.20)
�10.0 (10.85)
Total GERD Symptom and Severity score was the sum of the scores for the 12 individual symptoms (heartburn, dysphagia, belching/burping, regurgitation,
vomiting, hoarseness, coughing, choking, fullness during eating, anorexia, nausea, and abdominal pain) measured and recorded on the electronic case report
forms. The symptom scores were rated on severity during the week preceding the visit. Baseline was the last nonmissing assessment before taking 12-week DB
study drug. GERD ¼ gastroesophageal reflux disease; ITT ¼ intention-to-treat; SD ¼ standard deviation.
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TABLE 4. GERD Symptom and Severity score by individual symptoms
Children ages 1–5 y
Children ages 6–11 y
All children 1–11 y
Symptom score
N
Baseline
Wk 12
% Imp
n
Baseline
Wk 12
% Imp
n
Baseline
Wk 12
% Imp
Total GERD score
Vomiting
Nausea
Hoarseness
Choking
Dysphagia
Anorexia
Abdominal pain
Heartburn
Regurgitation
Fullness during eating
Belch/burp
Coughing
62
24
23
17
12
16
14
41
18
33
35
50
40
19.7
1.7
1.3
0.9
0.8
0.8
1.1
2.2
1.0
2.2
2.0
3.0
2.8
7.7
0.6
0.3
0.3
0.3
0.2
0.3
0.6
0.4
0.8
0.7
1.6
1.6
53.5
79.9
84.0
92.2
70.8
92.0
75.7
73.8
70.8
69.5
66.7
43.6
38.0
58
11
27
20
7
12
18
41
31
33
32
33
34
18.8
0.6
1.5
1.1
0.4
0.6
1.2
2.8
2.0
2.0
2.0
2.4
2.3
9.6
0.1
0.8
0.6
0.2
0.3
0.4
1.3
0.8
0.8
0.9
2.0
1.6
37.2
100.0
79.3
69.2
94.3
60.8
68.1
65.6
69.0
64.4
62.7
31.1
36.3
120
35
50
37
19
28
32
82
49
66
67
83
74
19.3
1.2
1.4
1.0
0.6
0.7
1.1
2.5
1.5
2.1
2.0
2.7
2.6
8.6
0.4
0.5
0.4
0.2
0.3
0.3
1.0
0.6
0.8
0.8
1.8
1.6
45.6
86.2
81.5
79.7
79.5
78.6
71.4
69.7
69.7
67.0
64.8
38.6
37.2
GERD ¼ gastroesophageal reflux disease; n ¼ size of subsample.
vomiting and abdominal pain (19% each) were more frequent in the
20-mg dose group (Table 6). When analyzed by weight cohorts, the
incidence of TEAEs was generally similar, with the exception
of abdominal pain and headache, which were reported only in
children in the high-weight cohort (Table 5). A greater proportion
(28%) of children in the 20-mg dose group experienced TEAEs
considered related to the study drug compared with the other dose
groups (11%–14%). There were no deaths reported during the
study.
Overall, 53 (42%) children had TEAEs that were considered
by the investigator as mild in severity, 36 (28%) children had
TEAEs that were considered as moderate, and 7 (6%) children had
severe TEAEs. Severe TEAEs included abdominal pain, nausea,
vomiting, bronchopneumonia, gastroenteritis, cough, and choking.
100
No change
10 mg low-weight cohort (N = 19)
Worse
Overall percentage shifts in
GERD symptom relief score (%)
Overall percentage shifts in
GERD symptom relief score (%)
5 mg low-weight cohort (N = 21)
Better
90
80
70
60
50
40
30
20
10
0
2
4
6
8
100
No change
80
70
60
50
40
30
20
10
2
4
Study week
No change
Worse
90
80
70
60
50
40
30
20
10
0
2
4
6
Study week
8
12
20 mg high-weight cohort (N = 43)
Overall percentage shifts in
GERD symptom relief score (%)
Overall percentage shifts in
GERD symptom relief score (%)
Better
6
Study week
10 mg high-weight cohort (N = 44)
100
Worse
90
0
12
Better
8
12
Better
100
No change
Worse
90
80
70
60
50
40
30
20
10
0
2
4
6
8
12
Study week
FIGURE 3. Overall percentage shifts in GERD symptom relief from baseline by visit (intention-to-treat population). GERD ¼ gastroesophageal
reflux disease.
804
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Efficacy and Safety of Rabeprazole in Pediatric Patients
TABLE 5. Global Treatment Satisfaction scores and CGI-I scores at the end of 12-week double-blind treatment (ITT population)
Rabeprazole treatment
Low-weight cohort
5 mg, N ¼ 21
Global Treatment Satisfaction score (%)
Wk 12, n
Poor (very dissatisfied)
Fair (dissatisfied)
Good (satisfied)
Excellent (very satisfied)
CGI-I score (%)
Wk 12, n
Poor (very dissatisfied)
Fair (dissatisfied)
Good (satisfied)
Excellent (very satisfied)
High-weight cohort
10 mg, N ¼ 19
10 mg, N ¼ 44
20 mg, N ¼ 43
Total, N ¼ 127
1
3
5
9
18
(6)
(17)
(28)
(50)
18
2 (11)
1 (6)
11 (61)
4 (22)
42
4 (10)
4 (10)
19 (45)
15 (36)
41
3 (7)
4 (10)
20 (49)
14 (34)
119
10 (8)
12 (10)
55 (46)
42 (35)
1
3
6
8
18
(6)
(17)
(33)
(44)
18
2 (11)
1 (6)
11 (61)
4 (22)
42
5 (12)
4 (10)
24 (57)
9 (21)
41
2 (5)
9 (22)
20 (49)
10 (24)
119
10 (8)
17 (14)
61 (51)
31 (26)
CGI-I ¼ Clinical Global Impression-I; ITT ¼ intention-to-treat.
Six (5%) children experienced a total of 7 treatment-emergent
serious adverse events: 3 respiratory infections, only 1 of which
was considered possibly related to the study drug; 2 GI infections,
considered not related to the study drug; 1 humerus fracture,
considered not related to the study drug; and 1 event of dehydration,
considered as doubtfully related to the study drug. With the
exception of 2 children with GI infections who were treated with
10-mg rabeprazole granule formulation (1 in each body weight
cohort), all of the other children who experienced serious adverse
events were from the 5-mg (low-weight cohort) dose group. Three
children withdrew from the study because of TEAEs, and all TEAEs
that led to study discontinuation were GI disorders (exacerbation of
vomiting, diarrhea, nausea, and abdominal pain). There were no
trends or clinically relevant changes seen in mean clinical laboratory or vital sign data.
classification and/or grade 0 on the Histological Features of Reflux
Esophagitis scale. Previous studies with rabeprazole in adults
using the Hetzel-Dent classification scale showed a similar healing
rate at week 4 and a slightly higher rate (92%) at week 8 (24). In this
study, endoscopic evaluation was only conducted at week 12;
however, the largest improvement in the frequency and severity
of GERD symptoms also occurred within the first 4 weeks of
treatment.
Pediatric GERD studies with a similar age range using other
PPIs reported healing rates of 70% to 100% during a treatment
period of 8 to 12 weeks (11,25,26); however, the present study is by
far the largest study conducted in this population and, unlike studies
with other PPIs, involves only children with endoscopically confirmed GERD who were reevaluated endoscopically at the conclusion of the study.
In the present study, clinical improvement was demonstrated
consistently with all applied assessment instruments, including the
Total GERD Symptom and Severity score, the Overall GERD
Symptom Relief score, the Global Treatment Satisfaction score,
and the CGI-I score. In addition, the endoscopic score improvement
was consistent with the clinical response; children with a larger
improvement in endoscopic scores showed a trend toward better
improvement on the Total GERD Symptom and Severity score.
Because changes in the GERD Symptom and Severity scores were
assessed weekly via an electronic handheld device, independent of
DISCUSSION
Rabeprazole is indicated for the treatment of GERD in adults
and adolescents. This was the first study to assess the efficacy and
safety of rabeprazole in the treatment of GERD in children 1 to
11 years old. Rabeprazole treatment resulted in endocopic/histologic healing and improvement of clinical symptoms. During the
12-week treatment period, 81% of children achieved endoscopic/
histologic healing, defined as grade 0 on the Hetzel-Dent
TABLE 6. Treatment-emergent adverse events reported in �10% of children in any dose group during the study (safety analysis set)
Rabeprazole treatment
Low-weight cohort
No. children with at least 1 TEAE
Vomiting
Cough
Abdominal pain
Diarrhea
5 mg, N ¼ 21,
n (%)
10 mg, N ¼ 19,
n (%)
16 (76)
2 (10)
3 (14)
0
3 (14)
15 (79)
2 (11)
4 (21)
0
4 (21)
High-weight cohort
10 mg, N ¼ 44,
n (%)
32
6
6
7
4
(73)
(14)
(14)
(16)
(9)
20 mg, N ¼ 43,
n (%)
33
8
5
8
3
(77)
(19)
(12)
(19)
(7)
Total, N ¼ 127,
n (%)
96
18
18
15
14
(76)
(14)
(14)
(12)
(11)
Incidence of TEAEs was based on the number of children having adverse events and not the number of events. TEAE ¼ treatment-emergent adverse event.
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endoscopic scoring, the results in this study suggest that endoscopic
score improvement may be associated with improvement in the
frequency and severity of clinical symptoms.
There was, however, little correlation between endoscopic
and histologic score improvement. Although 81% of children
showed an improvement by 1 (72% of children improved to
grade 0) on the Hetzel-Dent classification scale, only 57% showed
an improvement by 1 (38% of children improved to grade 0) on
the Histological Features of Reflux Esophagitis scale. There is no
obvious explanation for this discrepancy, but the individual reading
by the local pathologists may have introduced variations in the
interpretation of biopsies.
Before this study, other PPIs were proven effective in this
patient population, and thus it was not ethical to include a placebo
arm to assess the spontaneous response rate. This is a major
limitation in the design of this study; however, the high-endoscopic/histologic healing rate and the association between an
improved endoscopic score and improved clinical symptom score
suggest that a placebo effect was not a major determining factor in
the outcome.
No deaths occurred in this study. No dose-response relation
was observed with respect to TEAEs. Overall, the number and the
rate of TEAEs commonly associated with rabeprazole treatment
were similar across all of the dose groups, except the 20-mg dose
group, which reported a slightly higher rate of vomiting and
abdominal pain. The safety data derived from this study are similar
to those observed using other PPIs studied in children of different
age groups (1–17 years) (27–30). The study showed that 5 mg once
daily and 10 mg once daily were the lowest effective doses in
pediatric patients weighing <15 kg and those weighing >15 kg,
respectively.
CONCLUSIONS
Rabeprazole granules were effective and safe for the endoscopic/histologic healing and improvement of GERD symptoms in
pediatric patients 1 to 11 years of age. The safety findings in this
population of children with endoscopically proven GERD were
consistent with the known safety profile of rabeprazole. No new
safety findings were observed.
Acknowledgments: The authors thank Shruti Shah, PhD (SIRO
Clinpharm Pvt Ltd), for providing writing assistance and Bradford
Challis, PhD (Janssen Research & Development, LLC), for
providing additional editorial and scientific support for this
manuscript. The authors thank Dr Andrew Mulberg for his
contributions to the study and for providing review of the
manuscript during the time of his employment at Janssen. The
authors thank the study participants without whom this study would
not have been accomplished as well as the following investigators
for their participation in this study. Belgium: Michele Scaillon;
Patrick Bontems; Samy Cadranel; Laurence Muyshont; Etienne
Sokal; Massimiliano Paganelli; Francoise Smets; Xavier
Stephenne; Yvan Vandenplas; Thierry Devreker; Bruno Hauser;
André Vertruyen; Frederic De Meulder. Denmark: Steffen Husby;
Rikke Neess Pedersen; Jorgen Thorup; Gert Fonnest. France:
Christophe Dupont; Nicolas Kalach; Claire Spyckerelle. India:
Hemant Jain; Ashish Dubey; Nirbhay Mehta; Gal Singh Patel;
Atul Shende; Sharad Thora; Palakurthy Murali Krishna; Jyanthi
Kaliyanan. Israel: Arie Levine; Tzili Zangen; Avi On; Abozaid
Said; Raanan Shamir; Corina Hartman; Yoram Rosenbach;
Rivka Shapiro-Preminger; Noam Zevit; Ron Shaoul; Orly
Eshach-Adiv; Sarit Peleg; Irit Rosen; Dan Turner; Elena
Rachman; Ari Silbermintz. Italy: Diego Falchetti; Salvatore
Argento; Costantino De Giacomo; Valentina Mancini; Claudio
806
Volume 57, Number 6, December 2013
Romano; Donatella Comito; Valeria Ferraù; Annamaria Staiano;
Paola Coccorullo; Erasmo Miele; Dario Ummarino. Poland:
Wojciech Cichy; Iwona Ignys; Beata Klincewicz; Aleksandra
Lisowska; Jaroslaw Walkowiak; Ewa Hapyn; Barbara Buzalska;
Hanna Gaszewska-Ladniak; Joanna Pawlowska; Barbara Iwanczak;
Franciszek Iwanczak; Elzbieta Krzesiek; Krzysztof Matusiewicz;
Krystyna Mowszet; Tomasz Pytrus; Maciej Kaczmarski;
Katarzyna Kondej-Muszynska; Elzbieta Matuszewska; Katarzyna Sidor; Miroslawa Uscinowicz; Jaroslaw Kierkus; Maciej
Dadalski; Grzegorz Oracz; Bartosz Korczowski; Artur Bijos;
Radoslawa Jakobiec; Wieslaw Lewanowicz; Malgorzata Klimza;
Ewa Tomecka; Anna Karolina Obuchowicz; Agnieszka
Kaczmaryk; Joanna Kula-Gradzik; Marta Slimok; Krystyna
Wasowska-Krolikowska; Beata Gebora-Kowalaks; Malgorzata
Modzelewska-Holynska; Ewa Toporowska-Kowalska. South
Africa: Ismail Mitha; Haroon Mohammed Mitha; Farahnaz
Natha; Shahid Wadvalla; Hester C. Schuman; Jacomina C.F. Du
Preez; Isak Mulder; Ca Steyn; Dina Johanna Van Aswegen; Jan
Vermeulen; Robin Alexander Brown; Gerrit Stephanus De Villiers;
Shahid Wadvalla; Haroon Mohammed. United States of America:
Phyllis Bishop; Kim Adcock; Michael Nowicki; Paul Parker;
Jeffrey Bornstein; Reinaldo Figueroa-Colon; Devendra Mehta;
Karen Crissinger; Donna Kowalski; Betty Madison; Mary
Francisco; Francis H. Fischer; Kimberley A. Hunt; Anna M.
Johnson; Joseph A. Ley; Nicole M. Miller; Christopher M.
Morelock; Rhonda Ragsdale; Lori L. Ray; Dallas N. Shone;
Stephanie R. Tipton; Maria Valente; Tara N. Williams; David
Gremse; Ibrahim Haddad; Rima Jibaly; George Zureikat; Isaac
Melamed; Lynette Driscoll; Angela McDonald; Kevin Patrick
O’Brien; Jeffrey Neal Rosenweig; Sudipta Misra; Marek
Lukacik; Christine Nguyen; Sarah Boushey; J. Antonio Quiros;
Elizabeth A. Ruben; Edward Patterson; Marian Pfefferkorn; Mark
Corkins; Joseph Croffie; Joseph Fitzgerald; Sandeep Gupta; Joel
Lim; Girish Subbarao; Azim Qureshi; Amy Longenecker; Amyee
McMonagle; Jennifer Stokes; Sarah Sturgis; Julie Vallati; Heidi
Watts; Jyoti Ramakrishna; Jay Fong; Smita Shah; Donald Wayne
Laney; Randall Douglas McClellan; Janice Sullivan; Carmen
Condurache; Robert Dillard; Angela M. Jeffries; Ronald Morton;
Thomas Stephen; John Stutts; Vasundhara Tolia; Jerry Tomasovic;
Joseph Ibarguen-Secchia; Eduardo Tron; Dean R. Focht III; Martin
Maksimak; John Murphy Peters; John Tung; Edwin Lopez-Bernard;
April Ulmer; Joe Lynn Williams; James Doody; Cynthia J. Husk;
Karen Markham.
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2. Nelson SP, Chen EH, Syniar GM, et al. One-year follow-up of symptoms of gastroesophageal reflux during infancy. Pediatric Practice
Research Group. Pediatrics 1998;102:E67.
3. Kawahara H, Dent J, Davidson G. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology 1997;113:399–408.
4. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and
treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and
Nutrition. J Pediatr Gastroenterol Nutr 2001;32 (suppl 2):S1–31.
5. Gupta SK, Hassall E, Chiu YL, et al. Presenting symptoms of nonerosive and erosive esophagitis in pediatric patients. Dig Dis Sci 2006;
51:858–63.
6. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the
North American Society for Pediatric Gastroenterology, Hepatology,
and Nutrition (NASPGHAN) and the European Society for Pediatric
Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr
Gastroenterol Nutr 2009;49:498–547.
www.jpgn.org
FOR INDIVIDUAL USE ONLY. DISTRIBUTION OF THIS ARTICLE IS PROHIBITED BY THE PUBLISHER.
JPGN
Volume 57, Number 6, December 2013
7. Kim J, Keininger DL, Becker S, et al. Simultaneous development of the
Pediatric GERD Caregiver Impact Questionnaire (PGCIQ) in American
English and American Spanish. Health Qual Life Outcomes 2005;3:5.
8. Gremse DA. GERD in the pediatric patient: management considerations. MedGenMed 2004;6:13.
9. Gold BD, Freston JW. Gastroesophageal reflux in children: pathogenesis, prevalence, diagnosis, and role of proton pump inhibitors in
treatment. Paediatr Drugs 2002;4:673–85.
10. Tolia V, Youssef NN, Gilger MA, et al. Esomeprazole for the treatment
of erosive esophagitis in children: an international, multicenter, randomized, parallel-group, double-blind (for dose) study. BMC Pediatr
2010;10:41.
11. Franco MT, Salvia G, Terrin G, et al. Lansoprazole in the treatment of
gastro-oesophageal reflux disease in childhood. Dig Liver Dis 2000;
32:660–6.
12. Hassall E, Israel D, Shepherd R, et al. Omeprazole for treatment of
chronic erosive esophagitis in children: a multicenter study of efficacy,
safety, tolerability and dose requirements. International Pediatric Omeprazole Study Group. J Pediatr 2000;137:800–7.
13. ACIPHEX (rabeprazole sodium) [package insert]. Tokyo, Japan: Eisai
Company Ltd; 2007.
14. PARIET (rabeprazole sodium) [package insert]. London, UK: Eisai Ltd;
2007.
15. Caos A, Breiter J, Perdomo C, et al. Long-term prevention of erosive or
ulcerative gastro-oesophageal reflux disease relapse with rabeprazole 10
or 20 mg vs. placebo: results of a 5-year study in the United States.
Aliment Pharmacol Ther 2005;22:193–202.
16. Maiti R, Jaida J, Israel PL, et al. Rabeprazole and esomeprazole in mildto-moderate erosive gastroesophageal reflux disease: a comparative
study of efficacy and safety. J Pharmacol Pharmacother 2011;2:
150–7.
17. Zannikos PN, Doose DR, Leitz GJ, et al. Pharmacokinetics and tolerability of rabeprazole in children 1 to 11 years old with gastroesophageal
reflux disease. J Pediatr Gastroenterol Nutr 2011;52:691–701.
18. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic
esophagitis after treatment with omeprazole. Gastroenterology 1988;95:
903–12.
19. Miller G, Savary M. Is gastro-esophageal prolapse responsible for
lesions of the gastric mucosa? (proceedings). Minerva Gastroenterol
1977;23:42.
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Efficacy and Safety of Rabeprazole in Pediatric Patients
20. Williford WO, Krol WF, Spechler SJ. Development for and results of the
use of a gastroesophageal reflux disease activity index as an outcome
variable in a clinical trial. VA Cooperative Study Group on Gastroesophageal Reflux Disease (GERD). Control Clin Trials 1994;15:335–
48.
21. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of
treatment satisfaction, the Treatment Satisfaction Questionnaire for
Medication (TSQM), using a national panel study of chronic disease.
Health Qual Life Outcomes 2004;2:12.
22. Busner J, Targum SD. The clinical global impressions scale: applying a
research tool in clinical practice. Psychiatry (Edgmont) 2007;4:28–37.
23. Heartburn in-depth report. health.nytimes.com/health/guides/symptoms/
heartburn/print.html. Accessed May 14, 2013.
24. Dekkers CP, Beker JA, Thjodleifsson B, et al. Double-blind comparison
[correction of Double-blind, placebo-controlled comparison] of rabeprazole 20 mg vs. omeprazole 20 mg in the treatment of erosive or
ulcerative gastro-oesophageal reflux disease. The European Rabeprazole Study Group. Aliment Pharmacol Ther 1999;13:49–57.
25. Tolia V, Bishop PR, Tsou VM, et al. Multicenter, randomized, doubleblind study comparing 10, 20 and 40 mg pantoprazole in children (5-11
years) with symptomatic gastroesophageal reflux disease. J Pediatr
Gastroenterol Nutr 2006;42:384–91.
26. Tolia V, Gilger MA, Barker PN, et al. Healing of erosive esophagitis and
improvement of symptoms of gastroesophageal reflux disease after
esomeprazole treatment in children 12 to 36 months old. J Pediatr
Gastroenterol Nutr 2010;51:593–8.
27. Prevacid (lansoprazole) Deerfield, IL: Takeda Pharmaceuticals
America. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/
020406s076,021428s023lbl.pdf. Accessed February 14, 2012
28. Protonix (pantoprazole sodium). Sellersville, PA: Teva Pharmaceuticals. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/
020987s041,022020s005lbl.pdf. Accessed February 14, 2012
29. Nexium (esomeprazole magnesium). Wilmington, DE: AstraZenca Pharmaceuticals. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/
022101s007,021153s038,021957s010lbl.pdf. Accessed February 14,
2012
30. Prilosec (omeprazole). Wilmington, DE: AstraZenca Pharmaceuticals.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022056s007,
019810s091lbl.pdf. Accessed February 14, 2012
807
FOR INDIVIDUAL USE ONLY. DISTRIBUTION OF THIS ARTICLE IS PROHIBITED BY THE PUBLISHER.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ACIPHEX
safely and effectively. See full prescribing information for ACIPHEX.
--------------------------DOSAGE FORMS AND STRENGTHS-------------------------- Delayed-Release Tablets: 20 mg (3)
 Delayed-Release Capsules: 5 mg and 10 mg (3)
ACIPHEX® (rabeprazole sodium) Delayed-Release Tablets, for oral use
ACIPHEX® SprinkleTM (rabeprazole sodium) Delayed-Release Capsules, for oral
use
Initial U.S. Approval: 1999
--------------------------------------CONTRAINDICATIONS--------------------------------- History of hypersensitivity to rabeprazole (4)
--------------------------------WARNINGS AND PRECAUTIONS------------------------ Symptomatic response to therapy with rabeprazole does not preclude the presence
of gastric malignancy (5.1).
 Use with warfarin: Monitor for increases in INR and prothombin time (5.2).
 Acute interstitial nephritis has been observed in patients taking PPIs (5.3).
 Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g., longer than
3 years) may lead to malabsorption or a deficiency of cyanocobalamin (5.4).
 PPI therapy may be associated with increased risk of Clostridium difficile associated
diarrhea (5.5).
 Bone fracture: Long-term and multiple daily dose PPI therapy may be associated
with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine
(5.6).
 Hypomagnesemia has been reported rarely with prolonged treatment with PPIs
(5.7).
------------------------------RECENT MAJOR CHANGES------------------------------- Contraindications (4)
12/2014
 Warnings and Precautions; Acute Interstitial Nephritis (5.3)
12/2014
 Warnings and Precautions; Cyanocobalamin (vitamin B-12)
Deficiency (5.4)
12/2014
-----------------------------------INDICATIONS AND USAGE----------------------------ACIPHEX is a proton-pump inhibitor (PPI) indicated in adults for:
 Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) (1.1)
 Maintenance of Healing of Erosive or Ulcerative GERD (1.2)
 Treatment of Symptomatic GERD (1.3)
 Healing of Duodenal Ulcers (1.4)
 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
(1.5)
 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison
Syndrome (1.6)
---------------------------------------ADVERSE REACTIONS-------------------------------- In the adult studies (4 to 8 weeks), adverse reactions that occurred at a rate greater
than 2% and greater than placebo included pain, pharyngitis, flatulence,
infection, and constipation (6.1).
 In studies of pediatric and adolescent patients (ages 1 to 16 years, and up to
36 weeks exposure) adverse reactions that occurred at a rate of ≥5% of patients
included abdominal pain, diarrhea, and headache (6.1).
In adolescent patients 12 years of age and older for:
 Short-term treatment of Symptomatic GERD (1.7)
In pediatric patients 1 to 11 years of age for:
 Treatment of GERD (1.8)
-------------------------------DOSAGE AND ADMINISTRATION-------------------------ACIPHEX Delayed-Release Tablets should be swallowed whole. The tablets should
not be chewed, crushed, or split (2.10).
To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-----------------------------------------DRUG INTERACTIONS------------------------------ Increased INR and prothrombin times have been reported with concomitant use
with warfarin. Patients need to be monitored (7.2).
 Rabeprazole has been shown to inhibit cyclosporine metabolism in vitro (7.3).
 ACIPHEX inhibits gastric acid secretion and may interfere with the absorption of
drugs where gastric pH is an important determinant of bioavailability (e.g.,
ketoconazole, iron salts, digoxin, and mycophenolate mofetil) (7.4).
● ACIPHEX may reduce the plasma levels of atazanavir (7.4).
 Methotrexate: ACIPHEX may increase serum level of methotrexate (7.7).
ACIPHEX Sprinkle Delayed-Release Capsules should be opened and the granule
contents sprinkled on a spoonful of soft food or liquid (e.g., applesauce). Whole dose
should be taken within 15 minutes of being sprinkled. The granules should not be
chewed or crushed. Dose should be taken 30 minutes before a meal (2.10).
Healing of Erosive or Ulcerative Gastroesophageal
Reflux Disease (GERD) (2.1)
Maintenance of Healing of Erosive or Ulcerative GERD
(2.2) *studied for 12 months
Treatment of Symptomatic GERD in Adults (2.3)
20 mg once daily for
4 to 8 weeks
20 mg once daily*
20 mg once daily for 4
weeks
Healing of Duodenal Ulcers (2.4)
20 mg once daily after
morning meal for up
to 4 weeks
Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer
Recurrence (2.5)
All three medications
Three Drug Regimen:
ACIPHEX 20 mg
should be taken twice
Amoxicillin 1000 mg
daily with morning
Clarithromycin 500 mg
and evening meals for
7 days.
Starting dose 60 mg once
Treatment of Pathological Hypersecretory
daily then adjust to
Conditions, Including Zollinger-Ellison Syndrome
(2.6)
patient needs
20 mg once daily for up
Treatment of Symptomatic GERD in Adolescents
12 Years of Age and Older (2.7)
to 8 weeks
Treatment of GERD in 1- to 11-Year-Olds (2.8)
Less than 15 kg: 5 mg
once daily (with the
option to increase to
10 mg once daily)
15 kg or greater: 10 mg
once daily for up to
12 weeks
-----------------------------------USE IN SPECIFIC POPULATIONS--------------------Pregnancy: Based on animal data, may cause fetal harm (8.1).
Studies conducted do not support the use of ACIPHEX or the treatment of GERD
in pediatric patients younger than 1 year of age (8.4).

The safety and efficacy of ACIPHEX for the other adult indications have not been
established for pediatric patients (8.4).


See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: 12/2014
FOR INDIVIDUAL USE ONLY. DISTRIBUTION OF THIS ARTICLE IS PROHIBITED BY THE PUBLISHER.
FULL PRESCRIBING INFORMATION: CONTENTS*
1
2
3
4
5
6
INDICATIONS AND USAGE
1.1 Healing of Erosive or Ulcerative GERD in Adults
1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults
1.3 Treatment of Symptomatic GERD in Adults
1.4 Healing of Duodenal Ulcers in Adults
1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer
Recurrence in Adults
1.6 Treatment of Pathological Hypersecretory Conditions, Including ZollingerEllison Syndrome in Adults
1.7 Short-term Treatment of Symptomatic GERD in Adolescent Patients
12 Years of Age and Older
1.8 Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
DOSAGE AND ADMINISTRATION
2.1 Healing of Erosive or Ulcerative GERD in Adults
2.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults
2.3 Treatment of Symptomatic GERD in Adults
2.4 Healing of Duodenal Ulcers in Adults
2.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer
Recurrence in Adults
2.6 Treatment of Pathological Hypersecretory Conditions, Including ZollingerEllison Syndrome in Adults
2.7 Short-term Treatment of Symptomatic GERD in Adolescent Patients
12 Years of Age and Older
2.8 Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
2.9 Elderly, Renal, and Hepatic Impaired Patients
2.10 Administration Recommendations
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
5.1 Presence of Gastric Malignancy
5.2 Concomitant Use with Warfarin
5.3 Acute Interstitial Nephritis
5.4 Cyanocobalamin (vitamin B-12) Deficiency
5.5 Clostridium difficile Associated Diarrhea
5.6 Bone Fracture
5.7 Hypomagnesemia
5.8 Concomitant Use of ACIPHEX with Methotrexate
ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2 Postmarketing Experience
DRUG INTERACTIONS
7.1 Drugs Metabolized by CYP450
7.2 Warfarin
7.3 Cyclosporine
7.4 Compounds Dependent on Gastric pH for Absorption
7.5 Drugs Metabolized by CYP2C19
7.6 Combined Administration with Clarithromycin
7.7 Methotrexate
7.8 Clopidogrel
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Gender
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Healing of Erosive or Ulcerative GERD in Adults
14.2 Long-term Maintenance of Healing of Erosive or Ulcerative GERD in
Adults
14.3 Treatment of Symptomatic GERD in Adults
14.4 Healing of Duodenal Ulcers in Adults
14.5 Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or
Symptomatic Non-Ulcer Disease in Adults
14.6 Pathological Hypersecretory Conditions, Including Zollinger-Ellison
Syndrome
14.7 Pediatric GERD
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
7
2
FOR INDIVIDUAL USE ONLY. DISTRIBUTION OF THIS ARTICLE IS PROHIBITED BY THE PUBLISHER.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
1.1 Healing of Erosive or Ulcerative GERD in Adults
ACIPHEX is indicated for short-term (4 to 8 weeks) treatment in the healing
and symptomatic relief of erosive or ulcerative gastroesophageal reflux
disease (GERD). For those patients who have not healed after 8 weeks of
treatment, an additional 8-week course of ACIPHEX may be considered.
1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults
ACIPHEX is indicated for maintaining healing and reduction in relapse rates
of heartburn symptoms in patients with erosive or ulcerative gastroesophageal
reflux disease (GERD Maintenance). Controlled studies do not extend beyond
12 months.
1.3 Treatment of Symptomatic GERD in Adults
ACIPHEX is indicated for the treatment of daytime and nighttime heartburn
and other symptoms associated with GERD in adults for up to 4 weeks.
1.4 Healing of Duodenal Ulcers in Adults
ACIPHEX is indicated for short-term (up to four weeks) treatment in the
healing and symptomatic relief of duodenal ulcers. Most patients heal within
four weeks.
1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal
Ulcer Recurrence in Adults
ACIPHEX, in combination with amoxicillin and clarithromycin as a three
drug regimen, is indicated for the treatment of patients with H. pylori infection
and duodenal ulcer disease (active or history 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 (14.5) and Dosage and
Administration (2.5)].
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 (12.2) and the clarithromycin package insert, Clinical
Pharmacology (12.2)].
1.6 Treatment of Pathological Hypersecretory Conditions, Including
Zollinger-Ellison Syndrome in Adults
ACIPHEX is indicated for the long-term treatment of pathological
hypersecretory conditions, including Zollinger-Ellison syndrome.
1.7 Short-term Treatment of Symptomatic GERD in Adolescent
Patients 12 Years of Age and Older
ACIPHEX is indicated for the treatment of symptomatic GERD in adolescents
12 years of age and above for up to 8 weeks.
1.8 Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
ACIPHEX is indicated for treatment of GERD in children 1 to 11 years of age
for up to 12 weeks.
2
DOSAGE AND ADMINISTRATION
2.1 Healing of Erosive or Ulcerative GERD in Adults
The recommended adult oral dose is one ACIPHEX 20 mg Delayed-Release
tablet to be taken once daily for four to eight weeks [see Indications and
Usage (1.1)]. For those patients who have not healed after 8 weeks of
treatment, an additional 8-week course of ACIPHEX may be considered.
2.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults
The recommended adult oral dose is one ACIPHEX 20 mg Delayed-Release
tablet to be taken once daily. Controlled studies do not extend beyond
12 months [see Indications and Usage (1.2)].
2.3 Treatment of Symptomatic GERD in Adults
The recommended adult oral dose is one ACIPHEX 20 mg Delayed-Release
tablet to be taken once daily for 4 weeks [see Indications and Usage (1.3)]. If
symptoms do not resolve completely after 4 weeks, an additional course of
treatment may be considered.
2.4 Healing of Duodenal Ulcers in Adults
The recommended adult oral dose is one ACIPHEX 20 mg Delayed-Release
tablet to be taken once daily after the morning meal for a period up to four
weeks [see Indications and Usage (1.5)]. Most patients with duodenal ulcer
heal within four weeks. A few patients may require additional therapy to
achieve healing.
2.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal
Ulcer Recurrence in Adults
TABLE 1
THREE DRUG REGIMENa
ACIPHEX
Delayed-Release
Tablet
20 mg
Twice Daily for 7 Days
Amoxicillin
1000 mg
Twice Daily for 7 Days
Clarithromycin
500 mg
Twice Daily for 7 Days
All three medications should be taken twice daily with the morning and
evening meals.
a
It is important that patients comply with the full 7-day regimen [see
Clinical Studies (14.5)].
2.6 Treatment of Pathological Hypersecretory Conditions, Including
Zollinger-Ellison Syndrome in Adults
The dosage of ACIPHEX in patients with pathologic hypersecretory
conditions varies with the individual patient. The recommended adult oral
starting dose is 60 mg once daily. Doses should be adjusted to individual
patient needs and should continue for as long as clinically indicated. Some
patients may require divided doses. Doses up to 100 mg QD and 60 mg BID
have been administered. Some patients with Zollinger-Ellison syndrome have
been treated continuously with ACIPHEX for up to one year.
2.7 Short-term Treatment of Symptomatic GERD in Adolescent
Patients 12 Years of Age and Older
The recommended oral dose for adolescents 12 years of age and older is one
20 mg Delayed-Release Tablet once daily for up to 8 weeks [see Use in
Specific Populations (8.4) and Clinical Studies (14.7)].
2.8 Treatment of GERD in Pediatric Patients 1 to 11 Years of Age
The recommended dosage of ACIPHEX Sprinkle for pediatric patients 1 to
11 years of age by body weight is:

Less than 15 kg: 5 mg once daily for up to 12 weeks with the
option to increase to 10 mg if inadequate response [see Clinical
Studies (14.7)].

15 kg or more: 10 mg once daily for up to 12 weeks [see Clinical
Studies (14.7)].
2.9 Elderly, Renal, and Hepatic Impaired Patients
No dosage adjustment is necessary in elderly patients, in patients with renal
disease, or in patients with mild to moderate hepatic impairment.
Administration of rabeprazole to patients with mild to moderate liver
impairment resulted in increased exposure and decreased elimination. Due to
the lack of clinical data on rabeprazole in patients with severe hepatic
impairment, caution should be exercised in those patients.
2.10 Administration Recommendations
TABLE 2
ADMINISTRATION RECOMMENDATIONS
Formulation
DelayedRelease
Tablet
DelayedRelease
Capsule
Population
Adults and
adolescents
12 years of age
and older
Pediatric
patients 1 to
11 years of age
Instructions
Swallow tablets whole. Do not chew,
crush, or split tablets.
Tablets can be taken with or without food.
The dose should be taken 30 minutes
before a meal.
The granules should not be chewed or
crushed. Open capsule and sprinkle entire
contents on a small amount of soft food
(e.g., applesauce, fruit, or vegetable based
baby food, or yogurt) or empty contents
into a small amount of liquid (e.g., infant
formula, apple juice, or pediatric
electrolyte solution). The whole dose
should be taken within 15 minutes of
preparation.
Food or liquid should be at or below room
temperature. Do not store mixture for
FOR INDIVIDUAL USE ONLY. DISTRIBUTION OF THIS ARTICLE IS PROHIBITED BY THE PUBLISHER.
3
future use.
3
DOSAGE FORMS AND STRENGTHS
ACIPHEX Delayed-Release Tablets are provided in strength of 20 mg.
ACIPHEX Sprinkle Delayed-Release Capsules are provided in strengths of
5 and 10 mg. The 5 mg strength is a transparent blue and opaque white No. 2
capsule. The cap of the capsule is imprinted with “↑” and the body is
imprinted with “ACX 5mg”. The 10 mg strength is a transparent yellow and
opaque white No. 2 capsule. The cap of the capsule is imprinted with “↑” and
the body is imprinted with “ACX 10mg”.
4
CONTRAINDICATIONS
ACIPHEX is contraindicated in patients with known hypersensitivity to
rabeprazole, substituted benzimidazoles, or to any component of the
formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic
shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria
[see Adverse Reactions (6)].
For information about contraindications of antibacterial agents
(clarithromycin and amoxicillin) indicated in combination with ACIPHEX,
refer to the Contraindications section of their package inserts.
5
WARNINGS AND PRECAUTIONS
5.1 Presence of Gastric Malignancy
Symptomatic response to therapy with rabeprazole does not preclude the
presence of gastric malignancy.
Patients with healed GERD were treated for up to 40 months with rabeprazole
and monitored with serial gastric biopsies. Patients without H. pylori infection
(221 of 326 patients) had no clinically important pathologic changes in the
gastric mucosa. Patients with H. pylori infection at baseline (105 of
326 patients) had mild or moderate inflammation in the gastric body or mild
inflammation in the gastric antrum. Patients with mild grades of infection or
inflammation in the gastric body tended to change to moderate, whereas those
graded moderate at baseline tended to remain stable. Patients with mild grades
of infection or inflammation in the gastric antrum tended to remain stable. At
baseline, 8% of patients had atrophy of glands in the gastric body and 15%
had atrophy in the gastric antrum. At endpoint, 15% of patients had atrophy of
glands in the gastric body and 11% had atrophy in the gastric antrum.
Approximately 4% of patients had intestinal metaplasia at some point during
follow-up, but no consistent changes were seen.
5.2 Concomitant Use with Warfarin
Steady state interactions of rabeprazole and warfarin have not been adequately
evaluated in patients. There have been reports of increased INR and
prothrombin time in patients receiving a proton pump inhibitor and warfarin
concomitantly. Increases in INR and prothrombin time may lead to abnormal
bleeding and even death. Patients treated with a proton pump inhibitor and
warfarin concomitantly may need to be monitored for increases in INR and
prothrombin time.
5.3 Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in patients taking PPIs including
ACIPHEX. Acute interstitial nephritis may occur at any point during PPI
therapy and is generally attributed to an idiopathic hypersensitivity reaction.
Discontinue ACIPHEX if acute interstitial nephritis develops [see
Contraindications (4)].
5.4 Cyanocobalamin (vitamin B-12) Deficiency
Daily treatment with any acid-suppressing medications over a long period of
time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin
(vitamin B-12) caused by hypo- or achlorhydria. Rare reports of
cyanocobalamin deficiency occurring with acid-suppressing therapy have
been reported in the literature. This diagnosis should be considered if clinical
symptoms consistent with cyanocobalamin deficiency are observed.
5.5 Clostridium difficile Associated Diarrhea
Published observational studies suggest that PPI therapy like ACIPHEX may
be associated with an increased risk of Clostridium difficile associated
diarrhea, especially in hospitalized patients. This diagnosis should be
considered for diarrhea that does not improve [see Adverse Reactions (6.2)].
Patients should use the lowest dose and shortest duration of PPI therapy
appropriate to the condition being treated.
Clostridium difficile associated diarrhea (CDAD) has been reported with use
of nearly all antibacterial agents. For more information specific to
antibacterial agents (clarithromycin and amoxicillin) indicated for use in
combination with ACIPHEX, refer to Warnings and Precautions sections of
those package inserts.
5.6 Bone Fracture
Several published observational studies in adults suggest that PPI therapy may
be associated with an increased risk for osteoporosis-related fractures of the
hip, wrist, or spine. The risk of fracture was increased in patients who
received high-dose, defined as multiple daily doses, and long-term PPI
therapy (a year or longer). Patients should use the lowest dose and shortest
duration of PPI therapy appropriate to the condition being treated. Patients at
risk for osteoporosis-related fractures should be managed according to
established treatment guidelines [see Dosage and Administration (2) and
Adverse Reactions (6.2)].
5.7 Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely
in patients treated with PPIs for at least three months, in most cases after a
year of therapy. Serious adverse events include tetany, arrhythmias, and
seizures. In most patients, treatment of hypomagnesemia required magnesium
replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with
medications such as digoxin or drugs that may cause hypomagnesemia (e.g.,
diuretics), healthcare professionals may consider monitoring magnesium
levels prior to initiation of PPI treatment and periodically [see Adverse
Reactions (6.2)].
5.8 Concomitant Use of ACIPHEX with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily
at high dose; see methotrexate prescribing information) may elevate and
prolong serum levels of methotrexate and/or its metabolite, possibly leading to
methotrexate toxicities. In high-dose methotrexate administration, a temporary
withdrawal of the PPI may be considered in some patients [see Drug
Interactions (7.7)].
6
ADVERSE REACTIONS
Worldwide, over 2900 patients have been treated with rabeprazole in Phase IIIII clinical trials involving various dosages and durations of treatment.
Because clinical trials are conducted under varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect the
rates observed in practice.
6.1 Clinical Studies Experience
Adults
The data described below reflect exposure to ACIPHEX in 1064 adult patients
exposed for up to 8 weeks. The studies were primarily placebo- and activecontrolled trials in adult patients with Erosive or Ulcerative Gastroesophageal
Reflux Disease (GERD), Duodenal Ulcers, and Gastric Ulcers. The population
had a mean age of 53 years (range 18-89 years) and had a ratio of
approximately 60% male: 40% female. The racial distribution was 86%
Caucasian, 8% African American, 2% Asian, and 5% other. Most patients
received either 10 mg, 20 mg, or 40 mg/day of ACIPHEX.
An analysis of adverse reactions appearing in ≥2% of ACIPHEX patients
(n=1064), and with a greater frequency than placebo (n=89) in controlled
North American and European acute treatment trials, revealed the following
adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3%
vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).
Three long-term maintenance studies consisted of a total of 740 adult patients;
at least 54% of adult patients were exposed to rabeprazole for 6 months and at
least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%)
and 241 (33%) patients received 10 mg and 20 mg of ACIPHEX, respectively,
while 169 (23%) patients received placebo and 83 (11%) received
omeprazole.
The safety profile of rabeprazole in the maintenance studies in adults was
consistent with what was observed in the acute studies.
Other adverse reactions seen in controlled clinical trials, which do not meet
the above criteria (≥2% of ACIPHEX-treated patients and greater than
placebo) and for which there is a possibility of a causal relationship to
rabeprazole, include the following: headache, abdominal pain, diarrhea, dry
mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis,
hepatic encephalopathy, myalgia, and arthralgia.
Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials
using combination therapy with rabeprazole plus amoxicillin and
clarithromycin (RAC), no adverse reactions unique to this drug combination
4
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were observed. In the U.S. multicenter study, the most frequently reported
drug related adverse reactions for patients who received RAC therapy for 7 or
10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%),
respectively.
No clinically significant laboratory abnormalities particular to the drug
combinations were observed.
For more information on adverse reactions or laboratory changes with
amoxicillin or clarithromycin, refer to their respective package prescribing
information, Adverse Reactions section.
Pediatric
In a multicenter, open-label study of adolescent patients 12 to 16 years of age
with a clinical diagnosis of symptomatic GERD or endoscopically proven
GERD, the adverse event profile was similar to that of adults. The adverse
reactions reported without regard to relationship to ACIPHEX that occurred in
≥2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%),
vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse
reactions that occurred in ≥2% of patients were headache (5.4%) and nausea
(1.8%). There were no adverse reactions reported in this study that were not
previously observed in adults.
In a two-part, randomized, multicenter, double-blind, parallel-group study,
127 pediatric patients 1 to 11 years of age with endoscopically proven GERD
received either 5 mg or 10 mg (<15 kg body weight) or 10 mg or 20 mg
(>15 kg body weight) rabeprazole. In this study, some patients were exposed
to rabeprazole for 36 weeks. Adverse reactions that occurred in ≥5% of
patients included abdominal pain (5%), diarrhea (5%), and headache (5%).
There were no adverse reactions reported in this study that were not
previously observed in trials of adolescents and adults.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use
of ACIPHEX. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure: sudden death;
coma, hyperammonemia; jaundice; rhabdomyolysis; disorientation and
delirium; anaphylaxis; angioedema; bullous and other drug eruptions of the
skin; severe dermatologic reactions, including toxic epidermal necrolysis
(some fatal), Stevens-Johnson syndrome, and erythema multiforme; interstitial
pneumonia; interstitial nephritis; TSH elevations; bone fractures;
hypomagnesemia and Clostridium difficile associated diarrhea. In addition,
agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and
thrombocytopenia have been reported. Increases in prothrombin time/INR in
patients treated with concomitant warfarin have been reported.
7
DRUG INTERACTIONS
7.1 Drugs Metabolized by CYP450
Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug
metabolizing enzyme system. Studies in healthy subjects have shown that
rabeprazole does not have clinically significant interactions with other drugs
metabolized by the CYP450 system, such as warfarin and theophylline given
as single oral doses, diazepam as a single intravenous dose, and phenytoin
given as a single intravenous dose (with supplemental oral dosing). Steady
state interactions of rabeprazole and other drugs metabolized by this enzyme
system have not been studied in patients.
7.2 Warfarin
There have been reports of increased INR and prothrombin time in patients
receiving proton pump inhibitors, including rabeprazole, and warfarin
concomitantly. Increases in INR and prothrombin time may lead to abnormal
bleeding and even death [see Warnings and Precautions (5.2)].
7.3 Cyclosporine
In vitro incubations employing human liver microsomes indicated that
rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar,
a concentration that is over 50 times higher than the C max in healthy volunteers
following 14 days of dosing with 20 mg of rabeprazole. This degree of
inhibition is similar to that by omeprazole at equivalent concentrations.
7.4 Compounds Dependent on Gastric pH for Absorption
Due to its effects on gastric acid secretion, rabeprazole can reduce the
absorption of drugs where gastric pH is an important determinant of their
bioavailability. Like with other drugs that decrease the intragastric acidity, the
absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and
mycophenolate mofetil (MMF) can decrease, while the absorption of drugs
such as digoxin can increase during treatment with ACIPHEX.
Concomitant treatment with rabeprazole (20 mg daily) and ketoconazole in
healthy subjects decreased the bioavailability of ketoconazole by 30% and
increased the AUC and Cmax for digoxin by 19% and 29%, respectively.
Therefore, patients may need to be monitored when such drugs are taken
concomitantly with rabeprazole. Co-administration of rabeprazole and
antacids produced no clinically relevant changes in plasma rabeprazole
concentrations.
Concomitant use of atazanavir and PPIs is not recommended. Coadministration of atazanavir with PPIs is expected to substantially decrease
atazanavir plasma concentrations and thereby reduce its therapeutic effect.
Co-administration of PPIs in healthy subjects and in transplant patients
receiving MMF has been reported to reduce the exposure to the active
metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF
solubility at an increased gastric pH. The clinical relevance of reduced MPA
exposure on organ rejection has not been established in transplant patients
receiving PPIs and MMF. Use ACIPHEX with caution in transplant patients
receiving MMF.
7.5 Drugs Metabolized by CYP2C19
In a clinical study in Japan evaluating rabeprazole in adult patients
categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid
suppression was higher in poor metabolizers as compared to extensive
metabolizers. This could be due to higher rabeprazole plasma levels in poor
metabolizers. Whether or not interactions of rabeprazole sodium with other
drugs metabolized by CYP2C19 would be different between extensive
metabolizers and poor metabolizers has not been studied.
7.6 Combined Administration with Clarithromycin
Combined administration consisting of rabeprazole, amoxicillin, and
clarithromycin resulted in increases in plasma concentrations of rabeprazole
and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.3)].
Concomitant administration of clarithromycin with other drugs can lead to
serious adverse reactions due to drug interactions [see Warnings and
Precautions in prescribing information for clarithromycin]. Because of these
drug interactions, clarithromycin is contraindicated for co-administration with
certain drugs [see Contraindications in prescribing information for
clarithromycin] [see Drug Interactions in prescribing information for
amoxicillin].
7.7 Methotrexate
Case reports, published population pharmacokinetic studies, and retrospective
analyses suggest that concomitant administration of PPIs and methotrexate
(primarily at high dose; see methotrexate prescribing information) may
elevate and prolong serum levels of methotrexate and/or its metabolite
hydroxymethotrexate. However, no formal drug interaction studies of
methotrexate with PPIs have been conducted [see Warnings and Precautions
(5.8)].
7.8 Clopidogrel
Concomitant administration of rabeprazole and clopidogrel in healthy subjects
had no clinically meaningful effect on exposure to the active metabolite of
clopidogrel [see Clinical Pharmacology (12.3)]. No dose adjustment of
clopidogrel is necessary when administered with an approved dose of
ACIPHEX.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies with ACIPHEX in pregnant
women. No evidence of teratogenicity was seen in animal reproduction
studies with rabeprazole at 13 and 8 times the human exposure at the
recommended dose for GERD, in rats and rabbits, respectively (see Animal
Data). Changes in bone morphology were observed in offspring of rats treated
with oral doses of a different PPI through most of pregnancy and lactation
(see Animal Data). Because of these findings, ACIPHEX should be used in
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Embryo-fetal developmental studies have been performed in rats at
intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of
11.8 µg•hr/mL, about 13 times the human exposure at the recommended oral
dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma
AUC of 7.3 µg•hr/mL, about 8 times the human exposure at the recommended
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oral dose for GERD) and have revealed no evidence of harm to the fetus due
to rabeprazole.
Administration of rabeprazole to rats in late gestation and during lactation at
an oral dose of 400 mg/kg/day (about 195 times the human oral dose based on
mg/m2) resulted in decreases in body weight gain of the pups.
A pre- and postnatal developmental toxicity study in rats with additional
endpoints to evaluate bone development was performed with a different PPI at
about 3.4 to 57 times an oral human dose on a body surface area basis.
Decreased femur length, width and thickness of cortical bone, decreased
thickness of the tibial growth plate, and minimal to mild bone marrow
hypocellularity were noted at doses of this PPI equal to or greater than 3.4
times an oral human dose on a body surface area basis. Physeal dysplasia in
the femur was also observed in offspring after in utero and lactational
exposure to the PPI at doses equal to or greater than 33.6 times an oral human
dose on a body surface area basis. Effects on maternal bone were observed in
pregnant and lactating rats in a pre- and postnatal toxicity study when the PPI
was administered at oral doses of 3.4 to 57 times an oral human dose on a
body surface area basis. When rats were dosed from gestational day 7 through
weaning on postnatal day 21, a statistically significant decrease in maternal
femur weight of up to 14% (as compared to placebo treatment) was observed
at doses equal to or greater than 33.6 times an oral human dose on a body
surface area basis.
8.3 Nursing Mothers
It is not known if ACIPHEX is excreted in human milk; however, rabeprazole
is present in rat milk. Because many drugs are excreted in milk, caution
should be exercised when ACIPHEX is administered to a nursing woman.
8.4 Pediatric Use
Symptomatic GERD in Adolescent Patients Greater or Equal to 12 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. The adverse event profile in
adolescent patients was similar to that of adults. The related reported adverse
reactions that occurred in ≥2% of patients were headache (5.4%) and nausea
(1.8%). There were no adverse reactions reported in these studies that were
not previously observed in adults.
GERD in Pediatric Patients 1 to 11 Years of Age
The use of ACIPHEX for treatment of GERD in pediatric patients 1 to
11 years of age is supported by a randomized, multicenter, double-blind
clinical trial which evaluated two dose levels of rabeprazole in 127 pediatric
patients with endoscopic and histologic evidence of GERD prior to study
treatment. Dosing was determined by body weight: Patients weighing 6.0 to
14.9 kg received either 5 or 10 mg and those weighing 15.0 kg or more
received 10 or 20 mg of ACIPHEX Sprinkle daily. After 12 weeks of
rabeprazole treatment, 81% of patients demonstrated esophageal mucosal
healing on endoscopic assessment. In patients who had esophageal mucosal
healing at 12 weeks and elected to continue for 24 more weeks of rabeprazole,
90% retained esophageal mucosal healing at 36 weeks. No prespecified
formal hypothesis testing for evaluation of efficacy was conducted. The
absence of a placebo group does not allow assessment of sustained efficacy
through 36 weeks. There were no adverse reactions reported in this study that
were not previously observed in adolescents or adults.
Neonates <1 Month and Preterm Infants <44 Weeks Corrected Gestational
Age
Use of ACIPHEX Sprinkle in neonates is strongly discouraged at this time for
the treatment of GERD, based on the risk of prolonged acid suppression and
lack of demonstrated safety and effectiveness in neonates.
Based on population pharmacokinetic analysis, the median (range) for the
apparent clearance (CL/F) was 1.05 L/h (0.0543-3.44 L/h) in neonates and
4.46 L/h (0.822-12.4 L/h) in patients 1 to 11 months of age following once
daily administration of oral ACIPHEX Sprinkle.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of ACIPHEX, 19% were
65 years and over, while 4% were 75 years and over. No overall differences in
safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences
in responses between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out.
8.6 Gender
Duodenal ulcer and erosive esophagitis healing rates in women are similar to
those in men. Adverse reactions and laboratory test abnormalities in women
occurred at rates similar to those in men.
10 OVERDOSAGE
Because strategies for the management of overdose are continually
evolving, it is advisable to contact a Poison Control Center to determine
the latest recommendations for the management of an overdose of any
drug. There has been no experience with large overdoses with rabeprazole.
Seven reports of accidental overdosage with rabeprazole have been received.
The maximum reported overdose was 80 mg. There were no clinical signs or
symptoms associated with any reported overdose. Patients with ZollingerEllison syndrome have been treated with up to 120 mg rabeprazole QD. No
specific antidote for rabeprazole is known. Rabeprazole is extensively protein
bound and is not readily dialyzable. In the event of overdosage, treatment
should be symptomatic and supportive.
Single oral doses of rabeprazole at 786 mg/kg and 1024 mg/kg were lethal to
mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal
to dogs. The major symptoms of acute toxicity were hypoactivity, labored
respiration, lateral or prone position, and convulsion in mice and rats and
watery diarrhea, tremor, convulsion, and coma in dogs.
11 DESCRIPTION
The active ingredient in ACIPHEX (rabeprazole sodium) Delayed-Release
Tablets and in ACIPHEX Sprinkle (rabeprazole sodium) Delayed-Release
Capsules is rabeprazole sodium, which is a proton pump inhibitor. It is a
substituted benzimidazole known chemically as 2-[[[4-(3-methoxypropoxy)3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H–benzimidazole sodium salt. It has
an empirical formula of C18H20N3NaO3S and a molecular weight of 381.42.
Rabeprazole sodium is a white to slightly yellowish-white solid. It is very
soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl
acetate and insoluble in ether and n-hexane. The stability of rabeprazole
sodium is a function of pH; it is rapidly degraded in acid media, and is more
stable under alkaline conditions. The structural figure is:
FIGURE 1
Symptomatic GERD in Infants 1 to 11 Months of Age
Studies conducted do not support the use of ACIPHEX Sprinkle for the
treatment of GERD in pediatric patients younger than 1 year of age.
In a randomized, multicenter, placebo-controlled withdrawal trial, infants 1 to
11 months of age with a clinical diagnosis of symptomatic GERD, or
suspected or endoscopically proven GERD, were treated up to 8 weeks in two
treatment periods. In the first treatment period (open-label), 344 infants
received 10 mg of ACIPHEX Sprinkle for up to 3 weeks. Infants with clinical
response were then eligible to enter the second treatment period, which was
double-blind and randomized. Two hundred sixty-eight infants were
randomized to receive either placebo or 5 mg or 10 mg ACIPHEX Sprinkle.
This study did not demonstrate efficacy based on assessment of frequency of
regurgitation and weight-for-age Z-score. Adverse reactions that occurred in
≥5% of patients in any treatment group and with a higher rate than placebo
included pyrexia (7%) and increased serum gastrin levels (5%). There were no
adverse reactions reported in this study that were not previously observed in
adolescents and adults.
ACIPHEX is available for oral administration as Delayed-Release, entericcoated tablets containing 20 mg of rabeprazole sodium. ACIPHEX Sprinkle is
available for oral administration as 5 mg and 10 mg rabeprazole sodium
Delayed-Release Capsules containing enteric coated granules.
Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone,
diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose,
hypromellose phthalate, magnesium stearate, mannitol, propylene glycol,
sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron
oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the
ink pigment.
6
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ACIPHEX Sprinkle Delayed-Release Capsules contain granules of
rabeprazole sodium in a hard hypromellose capsule. Inactive ingredients are
colloidal silicon dioxide, diacetylated monoglycerides, ethylcellulose,
hydroxypropyl cellulose, hypromellose phthalate, magnesium oxide,
magnesium stearate, mannitol, talc, titanium dioxide, carrageenan, potassium
chloride, FD&C Blue No. 2 Aluminum Lake (in the 5 mg capsule), FD&C
Yellow, No. 6 (in the 10 mg capsule), and gray printing ink.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 Pharmacodynamics
Antisecretory Activity
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
Basal Acid Output
(mmol/hr)
Stimulated Acid Output
(mmol/hr)
% Time Gastric pH>3
*(p<0.01 versus placebo)
ACIPHEX
(20 mg QD)
0.4*
Placebo
2.8
0.6*
13.3
65*
10
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
85.8±64.3*
678.5±216
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
ACIPHEX
20 mg QD
Day 1
Day 8
Placebo
Parameter
Day 1
Day 8
Mean AUC0-24
340.8*
176.9*
925.5
862.4
Acidity
Median trough
3.77
3.51
1.27
1.38
pH (23-hr)a
% Time Gastric
54.6*
68.7*
19.1
21.7
pH>3b
% Time Gastric
44.1*
60.3*
7.6
11.0
pH>4b
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 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 (13.1)].
AUC ACIDITY (MMOL•HR/L)
ACIPHEX VERSUS PLACEBO ON DAY 7
OF ONCE DAILY DOSING (MEAN±SD)
AUC
interval
(hrs)
08:00
13:00
13:00
19:00
19:00
22:00
22:00
08:00
AUC 0-24 155.5±90.6* 130.9±81*
hours
*(p<0.001 versus placebo)
10 mg
RBP
(N=24)
– 19.6±21.5*
Treatment
20 mg
40 mg
RBP
RBP
(N=24)
(N=24)
12.9±23*
7.6±14.7*
91.1±39.7
–
5.6±9.7*
8.3±29.8*
1.3±5.2*
95.5±48.7
–
0.1±0.1*
0.1±0.06*
0.0±0.02*
11.9±12.5
–
129.2±84*
109.6±67.2* 76.9±58.4*
479.9±165
Placebo
(N=24)
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.
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
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stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein,
parathyroid hormone, insulin, glucagon, renin, aldosterone, folliclestimulating 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
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.
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.
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 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 g/mL) to amoxicillin at
baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC
of 0.5 g/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)
H. pylori Positive
(Persistent)
Days of Clarithromycin
H. pylori
Post-Treatment
Total
RAC
Negative
Pretreatment
Number
Susceptibility Results
Therapy
Results
(Eradicated) b
S
Ib
Rb
No
MIC
b
7
Susceptible
129
103
2
0
1
23
7
Intermediateb
0
0
0
0
0
0
7
Resistantb
16
5
2
1
4
4
10
Susceptibleb
133
111
3
1
2
16
10
Intermediateb
0
0
0
0
0
0
10
Resistantb
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 g/mL, Intermediate (I) MIC = 0.5 g/mL,
Resistant (R) MIC 1 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 g/mL) to amoxicillin at baseline. The other two patients had baseline
H. pylori isolates with an amoxicillin MIC of 0.5 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 g/mL) were eradicated of H. pylori. No patients
developed amoxicillin-resistant H. pylori during therapy.
12.3 Pharmacokinetics
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.
Absorption: 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.
Distribution: Rabeprazole is 96.3% bound to human plasma proteins.
Metabolism: 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.
Elimination: 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.
Geriatric: 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 (8.5)].
Pediatric: 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
8
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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 8.4 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 (2.9)].
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, AUC 0-
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral
doses up to 100 mg/kg/day did not produce any increased tumor occurrence.
The highest tested dose produced a systemic exposure to rabeprazole (AUC)
of 1.40 µg•hr/mL, which is 1.6 times the human exposure (plasma AUC 0- =
0.88 µg•hr/mL) at the recommended dose for GERD (20 mg/day). In a 28week carcinogenicity study in p53+/- transgenic mice, rabeprazole at oral doses
of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates
of tumors but produced gastric mucosal hyperplasia at all doses. The systemic
exposure to rabeprazole at 200 mg/kg/day is about 17 to 24 times the human
exposure at the recommended dose for GERD. In a 104-week carcinogenicity
study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30,
and 60 mg/kg/day and females with 5, 15, 30, 60, and 120 mg/kg/day.
Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in
male and female rats and ECL cell carcinoid tumors in female rats at all doses
including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a
systemic exposure to rabeprazole (AUC) of about 0.1 µg•hr/mL, which is
about 0.1 times the human exposure at the recommended dose for GERD. In
male rats, no treatment related tumors were observed at doses up to
60 mg/kg/day producing a rabeprazole plasma exposure (AUC) of about
0.2 µg•hr/mL (0.2 times the human exposure at the recommended dose for
GERD).
Rabeprazole was positive in the Ames test, the Chinese hamster ovary cell
(CHO/HGPRT) forward gene mutation test, and the mouse lymphoma cell
(L5178Y/TK+/–) forward gene mutation test. Its demethylated-metabolite was
also positive in the Ames test. Rabeprazole was negative in the in vitro
Chinese hamster lung cell chromosome aberration test, the in vivo mouse
micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled
DNA synthesis (UDS) tests.
Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of
8.8 µg•hr/mL, about 10 times the human exposure at the recommended dose
for GERD) was found to have no effect on fertility and reproductive
performance of male and female rats.
13.2 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 postpartum 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.
14 CLINICAL STUDIES
14.1 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
N=27
20 mg
ACIPHEX
QD
N=25
40 mg
ACIPHEX
QD
N=26
Placebo
N=25
9
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4
63%*
8
93%*
*(p<0.001 versus placebo)
56%*
84%*
54%*
85%*
0%
12%
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 10
PERCENT OF PATIENTS WITHOUT RELAPSE IN HEARTBURN
FREQUENCY AND DAYTIME AND NIGHTTIME HEARTBURN
SEVERITY AT WEEK 52
Heartburn
Frequency
Study 1
Study 2
Daytime Heartburn
Severity
Study 1
TABLE 8
HEALING OF EROSIVE OR ULCERATIVE
GASTROESOPHAGEAL REFLUX DISEASE (GERD)
PERCENTAGE OF PATIENTS HEALED
ACIPHEX 20 mg QD
Week
N=167
4
59%*
8
87%*
*(p<0.001 versus ranitidine)
*(p<0.001 versus placebo)
Ranitidine 150 mg QID
N=169
36%
66%
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.
14.2 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:
Study 2
Nighttime
Heartburn Severity
Study 1
Study 2
ACIPHEX
10 mg
ACIPHEX
20 mg
Placebo
46/55
(84%)*
50/72
(69%)*
48/52
(92%)*
57/72
(79%)*
17/45
(38%)
22/79
(28%)
61/64
(95%)*
73/84
(87%)†
60/62
(97%)*
82/87
(94%)*
42/61
(69%)
67/90
(74%)
57/61
(93%)*
67/80
(84%)
60/61
(98%)*
79/87
(91%)†
37/56
(66%)
64/87
(74%)
* p0.001 versus placebo
†
0.001<p<0.05 versus placebo
14.3 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
HEARTBURN
RAB-USA-2
Figure 1:DAYTIME
Mean Daytime heartburn
scores RAB -SCORES
USA - 2
4
PLACEBO, n = 68
RAB 10mg, n = 64
RAB 20mg, n = 67
TABLE 9
PERCENT OF PATIENTS IN ENDOSCOPIC REMISSION
MEAN SCORE
3
2
1
Study 1
Week 4
Week 13
Week 26
Week 39
Week 52
Study 2
Week 4
Week 13
Week 26
Week 39
Week 52
COMBINED
STUDIES
Week 4
Week 13
Week 26
Week 39
Week 52
ACIPHEX
10 mg
N=66
83%*
79%*
77%*
76%*
73%*
N=93
89%*
86%*
85%*
84%*
77%*
ACIPHEX
20 mg
N=67
96%*
93%*
93%*
91%*
90%*
N=93
94%*
91%*
89%*
88%*
86%*
Placebo
N=159
N=160
N=169
87%*
83%*
82%*
81%*
75%*
94%*
92%*
91%*
89%*
87%*
42%
36%
31%
30%
29%
0
N=70
44%
39%
31%
30%
29%
N=99
40%
33%
30%
29%
29%
-14
-7
0
7
14
21
28
STUDY DAY
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe.
FIGURE 3: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-2
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Figure 2: Mean Nighttime heartburn scores RAB - USA - 2
4
3
MEAN SCORE
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).
PLACEBO, n = 68
RAB 10mg, n = 64
RAB 20mg, n = 67
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:
2
1
0
-14
-7
0
7
14
21
28
STUDY DAY
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe.
TABLE 12
FIGURE 4: MEAN
SCORES
Figure DAYTIME
3: Mean DaytimeHEARTBURN
heartburn scores RAB
- USA - 3 RAB-USA-3
4
HEALING OF DUODENAL ULCERS
PERCENTAGE OF PATIENTS HEALED
PLACEBO, n = 58
RAB 20mg, n = 59
Week
ACIPHEX
20 mg QD
N=102
Omeprazole
20 mg QD
N=103
2
4
69%
98%
61%
93%
MEAN SCORE
3
2
1
0
-14
-7
0
7
14
21
28
STUDY DAY
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe.
FIGURE 5: MEAN
HEARTBURN
SCORES
RAB-USA-3
Figure 4:NIGHTTIME
Mean Nighttime heartburn
scores RAB - USA
-3
4
PLACEBO, n = 58
RAB 20mg, n = 59
MEAN SCORE
3
2
1
0
-14
-7
0
7
14
21
28
STUDY DAY
Heartburn Scores: 0 = None, 1 = Slight, 2 = Moderate, 3 = Severe, 4 = Very Severe.
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).
14.4 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
ACIPHEX 20 mg
QD
N=34
2
44%
4
79%*
* p0.001 versus placebo
Week
ACIPHEX 40 mg
QD
N=33
42%
91%*
ACIPHEX and omeprazole were comparable in providing complete resolution
of symptoms.
14.5 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 PerProtocol (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
Per Protocola
Placebo
N=33
Intent-toTreatb
21%
39%
Per Protocola
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
95% Confidence
Interval for
the Treatment
Difference
(ACIPHEX Omeprazole)
(–6%, 22%)
(–3%, 15%)
Intent-toTreatb
Per Protocola
Intent-toTreatb
Treatment Group
Percent (%) of
Patients Cured
(Number of Patients)
7-day
10-day
RAC*
OAC
84.3%
81.6%
(N=166)
(N=179)
77.3%
73.3%
(N=194)
(N=206)
10-day
10-day
RAC*
OAC
86.0%
81.6%
(N=171)
(N=179)
78.1%
73.3%
(N=196)
(N=206)
3-day
10-day
RAC
OAC
29.9%
81.6%
(N=167)
(N=179)
27.3%
73.3%
(N=187)
(N=206)
Difference
(RAC – OAC)
[95% Confidence
Interval]
2.8
[- 5.2, 10.7]
4.0
[- 4.4, 12.5]
4.4
[- 3.3, 12.1]
4.8
[- 3.6, 13.2]
- 51.6
[- 60.6, - 42.6]
- 46.0
[- 54.8, - 37.2]
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a
Patients 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.
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.
14.6 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.
14.7 Pediatric GERD
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
16 HOW SUPPLIED/STORAGE AND HANDLING
ACIPHEX 20 mg is supplied as delayed-release light yellow enteric-coated
tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one
side.
Bottles of 30 (NDC 62856-243-30)
Bottles of 90 (NDC 62856-243-90)
Unit Dose Blisters Package of 100 (10 x 10) (NDC 62856-243-41)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature]. Protect from moisture.
ACIPHEX Sprinkle (5 mg) is supplied as transparent blue and opaque white
capsules containing enteric coated granules. Identification and strength (ACX
5mg) are imprinted on the body of the capsule. An arrow ( ↑) imprint on the
capsule cap indicates direction for opening a capsule.
Bottles of 30 (NDC 13551-205-01)
ACIPHEX Sprinkle (10 mg) is supplied as transparent yellow and opaque
white capsules containing enteric coated granules. Identification and strength
(ACX 10mg) are imprinted on the body of the capsule. An arrow (↑) imprint
on the capsule cap indicates direction for opening a capsule.
Bottles of 30 (NDC 13551-210-01)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature]. Protect from moisture.
17
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide).
How to Take ACIPHEX
Patients should be cautioned that ACIPHEX Delayed-Release Tablets should
be swallowed whole. The tablets should not be chewed, crushed, or split.
ACIPHEX can be taken with or without food.
ACIPHEX Sprinkle Delayed-Release Capsules should be opened and the
granule contents sprinkled on a small amount of soft food (e.g., applesauce,
fruit, or vegetable based baby food, or yogurt) or empty contents into a small
amount of liquid (e.g., infant formula, apple juice, or pediatric electrolyte
solution). Food or liquid should be at or below room temperature. The whole
dose should be taken within 15 minutes of being sprinkled. The granules
should not be chewed or crushed. The dose should be taken 30 minutes before
a meal. Do not store mixture for future use.
Advise patient to immediately report and seek care for diarrhea that does not
improve. This may be a sign of Clostridium difficile associated diarrhea [see
Warnings and Precautions (5.5)].
Healing Rate
at 12 weeks
Body Weight <15 kg
5 mg dose
10 mg dose
Erosivea
88%
83%
(7/8)
(5/6)
b
Non-erosive
78%
100%
(7/9)
(10/10)
a
Hetzel-Dent score ≥2
b
Hetzel-Dent score = 1
Body Weight ≥15 kg
10 mg dose
71%
(12/17)
81%
(17/21)
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.
15 REFERENCES
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.
12
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MEDICATION GUIDE
ACIPHEX® (a-se-feks)
(rabeprazole sodium)
Delayed-Release Tablets
ACIPHEX® SprinkleTM (a-se-feks spr-en-kle)
(rabeprazole sodium)
Delayed-Release Capsules
Read the Medication Guide that comes with ACIPHEX before you start taking it and each
time you get a refill. There may be new information. This Medication Guide does not
take the place of talking to your doctor about your medical condition or treatment.
What is the most important information I should know about ACIPHEX?
ACIPHEX may help your acid-related symptoms, but you could still have serious
stomach problems. Talk with your doctor.
ACIPHEX can cause serious side effects, including:

Diarrhea. ACIPHEX may increase your risk of getting severe diarrhea. This
diarrhea may be caused by an infection (Clostridium difficile) in your intestines.
Call your doctor right away if you have watery stool, stomach pain, and fever that
does not go away.

Bone fractures. People who take multiple daily doses of Proton Pump Inhibitor
(PPI) medicines for a long period of time (1 year or longer) may have an increased
risk of fractures of the hip, wrist, or spine. You should take ACIPHEX exactly as
prescribed, at the lowest dose possible for your treatment and for the shortest
time needed. Talk to your doctor about your risk of bone fracture if you take
ACIPHEX.
ACIPHEX can have other serious side effects. See “What are the possible side effects
of ACIPHEX?”
What is ACIPHEX?
ACIPHEX is a prescription medicine called a Proton Pump Inhibitor (PPI). ACIPHEX
reduces the amount of acid in your stomach.
ACIPHEX is used in adults:
 for up to 8 weeks to heal acid-related damage to the lining of the esophagus
(called erosive esophagitis or EE) and to relieve symptoms, such as heartburn
pain. If needed, your doctor may decide to prescribe another 8 weeks of ACIPHEX.
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
to maintain the healing of the esophagus and relief of symptoms related to EE. It
is not known if ACIPHEX is safe and effective if used longer than 12 months
(1 year).

for 4 weeks to treat daytime and nighttime heartburn and other symptoms that
happen with Gastroesophageal Reflux Disease (GERD).
GERD happens when acid in your stomach backs up into the tube (esophagus) that
connects your mouth to your stomach. This may cause a burning feeling in your
chest or throat, sour taste, or burping.

for up to 4 weeks for the healing and relief of duodenal ulcers. The duodenal area
is the area where food passes when it leaves the stomach.

for 7 days with certain antibiotic medicines to treat an infection caused by bacteria
called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The
infection needs to be treated to prevent the ulcers from coming back.

for the long-term treatment of conditions where your stomach makes too much
acid. This includes a rare condition called Zollinger-Ellison syndrome.
ACIPHEX is used in adolescents 12 years of age and older to treat symptoms of
Gastroesophageal Reflux Disease (GERD) for up to 8 weeks.
ACIPHEX is used in children 1 to 11 years of age to treat GERD for up to 12 weeks.
ACIPHEX is not effective in treating symptoms of GERD in children 1 month to
11 months of age.
ACIPHEX should not be used to treat GERD in babies younger than 1 month of age.
Who should not take ACIPHEX?
Do not take ACIPHEX if you:

are allergic to rabeprazole or any of the other ingredients in ACIPHEX. See the end
of this Medication Guide for a complete list of ingredients in ACIPHEX.

are allergic to any other Proton Pump Inhibitor (PPI) medicine.
What should I tell my doctor before taking ACIPHEX?
Before you take ACIPHEX tell your doctor if you:






have been told that you have low magnesium levels in your blood.
have liver problems.
have any allergies.
have any other medical conditions.
are pregnant or planning to become pregnant. It is not known if ACIPHEX can
harm your unborn baby.
are breastfeeding. It is not known if ACIPHEX passes into your breast milk. Talk to
your doctor about the best way to feed your baby if you take ACIPHEX.
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Tell your doctor about all the medicines you take, including prescription and
non-prescription medicines, vitamins, and herbal supplements. ACIPHEX may
affect how other medicines work, and other medicines may affect how ACIPHEX works.
Especially tell your doctor if you take:












atazanavir (Reyataz)
cyclosporine (Sandimmune, Neoral)
digoxin (Lanoxin)
ketoconazole (Nizoral)
warfarin (Coumadin)
theophylline (THEO-24 Thelair)
diazepam (Valium)
phenytoin (Dilantin)
an antibiotic that contains amoxicillin or clarithromycin
a “water pill” (diuretic)
methotrexate
mycophenolate mofetil (Cellcept)
Ask your doctor or pharmacist for a list of these medicines, if you are not sure.
Know the medicines that you take. Keep a list of them to show your doctor and
pharmacist when you get a new medicine.
How should I take ACIPHEX?

Take ACIPHEX exactly as prescribed. Your doctor will prescribe the dose that is
right for you and your medical condition. Do not change your dose or stop taking
ACIPHEX unless you talk to your doctor. Take ACIPHEX for as long as it is
prescribed even if you feel better.

ACIPHEX is usually taken one time each day. Your doctor will tell you the time of
day to take ACIPHEX, based on your medical condition.

ACIPHEX Tablets can be taken with or without food. Your doctor will tell you
whether to take this medicine with or without food based on your medical
condition.

Swallow each ACIPHEX Tablet whole with water. Do not chew, crush, or split
ACIPHEX Tablets. Tell your doctor if you cannot swallow tablets whole.

Take a dose of ACIPHEX Sprinkle Delayed-Release Capsules as follows:
o Take the dose 30 minutes before a meal.
o Open the capsule and sprinkle the contents onto a small amount of soft food
such as applesauce, fruit, or vegetable based baby food, or yogurt. You may
also empty the capsule contents into a small amount of infant formula, apple
juice, or a pediatric electrolyte solution such as Pedialyte®. The food or liquid
that you use should be at or below room temperature.
o Swallow the entire mixture. Do not chew or crush the granules.
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o Take the entire dose within 15 minutes. If you cannot take the dose within
15 minutes of preparing it, throw it away and prepare a new dose. Do not
save it for use later.

If you miss a dose of ACIPHEX, take it as soon as possible. If it is almost time for
your next dose, skip the missed dose and go back to your normal schedule. Do not
take 2 doses at the same time.

If you take too much ACIPHEX, call your doctor or Poison Control Center right
away, or go to the nearest hospital emergency room.

Your doctor may prescribe antibiotic medicines with ACIPHEX to help treat a
stomach infection and heal stomach (duodenal) ulcers that are caused by bacteria
called H. pylori. Make sure you read the patient information that comes with an
antibiotic before you start taking it.
What are the possible side effects of ACIPHEX?
ACIPHEX may cause serious side effects, including:

See “What is the most important information I should know about
ACIPHEX?”

Vitamin B-12 deficiency. ACIPHEX reduces the amount of acid in your stomach.
Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor
about the possibility of vitamin B-12 deficiency if you have been on ACIPHEX for a
long time (more than 3 years).

Low magnesium levels in your body. This problem can be serious. Low
magnesium can happen in some people who take a Proton Pump inhibitor (PPI)
medicine for at least 3 months. If low magnesium levels happen, it is usually after
a year of treatment. You may or may not have symptoms of low magnesium.
Tell your doctor right away if you have any of these symptoms:
 seizures
 dizziness
 abnormal or fast heart beat
 jitteriness
 jerking movements or shaking (tremors)
 muscle weakness
 spasms of the hands and feet
 cramps or muscle aches
 spasm of the voice box
Your doctor may check the level of magnesium in your body before you start
taking ACIPHEX, during treatment, or if you will be taking ACIPHEX for a long
period of time.
The most common side effects with ACIPHEX include:
 headache
 pain
 sore throat
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


gas
infection
constipation
The most common side effects with ACIPHEX in children include:
 stomach-area (abdomen) pain
 diarrhea
 headache
Other side effects:
Serious allergic reactions. Tell your doctor if you get any of the following symptoms
with ACIPHEX:
 rash
 face swelling
 throat tightness
 difficulty breathing
Your doctor may stop ACIPHEX if these symptoms happen.
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the side effects of ACIPHEX. For more information, ask your doctor or
pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store ACIPHEX?

Store ACIPHEX Tablets and ACIPHEX Sprinkle Delayed-Release Capsules in a dry
place at room temperature between 68F to 77F (20C to 25C).
Keep ACIPHEX and all medicines out of the reach of children.
General Information about ACIPHEX
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use ACIPHEX for a condition for which it was not prescribed. Do not give
ACIPHEX to other people, even if they have the same symptoms that you have. It may
harm them.
This Medication Guide summarizes the most important information about ACIPHEX. If
you would like more information, talk to your doctor. You can also ask your doctor or
pharmacist for information about ACIPHEX that is written for healthcare professionals.
For more information, go to http://www.aciphex.com/ or call 1-888-4-ACIPHEX.
17
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What are the ingredients in ACIPHEX?
Active ingredient: rabeprazole sodium
ACIPHEX Delayed-Release Tablets inactive ingredients: carnauba wax,
crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose,
hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium
hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the
coloring agent for the tablet coating. Iron oxide red is the ink pigment.
ACIPHEX Sprinkle Delayed-Release Capsules inactive ingredients: colloidal silicon
dioxide, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose,
hypromellose phthalate, magnesium oxide, magnesium stearate, mannitol, talc, titanium
dioxide, carrageenan, potassium chloride, FD&C Blue No.2 Aluminum Lake (in the 5 mg
capsule), FD&C Yellow, No. 6 (in the 10 mg capsule), and gray printing ink.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
AcipHex Sprinkle is Distributed by FSC Laboratories, Inc., Charlotte, NC 28210.
Revised December 2014
ACIPHEX® is a registered trademark of Eisai R&D Management Co., Ltd; ACIPHEX®
SprinkleTM is a trademark of Eisai R&D Management Co., Ltd, each of which is licensed to
Eisai Inc. All brand names are the trademarks of their respective owners.
18
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