Indications and Usage, Pediatric Patients (1.8) 03/2013

Dosage and Administration, Pediatric Patients (2.8) 03/2013

Warnings and Precautions, Clostridium difficile associated diarrhea (5.3) 10/2012

Warnings and Precautions, Concomitant use of ACIPHEX with Methotrexate (5.6) 05/2012

DOSAGE AND ADMINISTRATION

ACIPHEX Delayed-Release Tablets should be swallowed whole. The tablets should not be chewed, crushed or split (2.10).

ACIPHEX Sprinkle Delayed-Release Capsules should be opened and the granule contents sprinkled on a spoonful of soft food or liquid (e.g. apple sauce). 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).

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 [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. The recommended adolescent dosing is one ACIPHEX 20 mg Delayed-Release tablet to be taken once daily for 8 weeks.

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

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

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".

CONTRAINDICATIONS

Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation.

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with ACIPHEX, refer to the Contraindications section of their package inserts.

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 )

• PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea ( 5.3 )

• 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 ( 5.4 )

• Hypomagnesemia has been reported rarely with prolonged treatment with PPIs ( 5.5 )

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 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.

5.4 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)].

5.5 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)].

5.6 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)].

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 and digoxin) ( 7.4 )

• ACIPHEX may reduce the plasma levels of atazanavir ( 7.4 )

• Methotrexate: ACIPHEX may increase serum level of methotrexate ( 7.7 )

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 Cmax 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

Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and Cmax for digoxin of 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 proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.

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 (5.6)].

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.

USE IN SPECIFIC POPULATIONS

• 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 ).

8.1 Pregnancy

Pregnancy Category B

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. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Animal Data

Embryo-fetal development studies have been performed in rats at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11.8 mg *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 mg *hr/mL, about 8 times the human exposure at the recommended 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.

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.

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.

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.

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 Zollinger-Ellison 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.

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

ACIPHEX is available for oral administration as Delayed-Release, enteric-coated 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.

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.

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.

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.

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:

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 were observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. In a study of CYP2C19 genotyped subjects in Japan, poor metabolizers developed statistically significantly higher serum gastrin concentrations than extensive metabolizers.

Effects on Enterochromaffin-like (ECL) Cells

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females [see Nonclinical Toxicology (13.1)].

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 b-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6b-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 methodology1, 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 mg/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 mg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mg/mL.

For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

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 mg/mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mg/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 mg/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 (15mL) of applesauce, one Tablespoon (15mL) of yogurt, or when mixed with a small amount (5mL) 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

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 (2.7)].

Hepatic Disease: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC0-[?] and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.

No information exists on rabeprazole disposition in patients with severe hepatic impairment. Please refer to the Dosage and Administration (2.7) 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.

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 mg *hr/mL which is 1.6 times the human exposure (plasma AUC0-[?] = 0.88 mg *hr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week 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 17-24 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 mg *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 mg *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 mg *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 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25 or 150 mg/kg/day and dogs were dosed at 3, 10 or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.

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:

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):

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:

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 DAYTIME HEARTBURN SCORES RAB-USA-2

FIGURE 3: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-2

FIGURE 4: MEAN DAYTIME HEARTBURN SCORES RAB-USA-3

FIGURE 5: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-3

In addition, the combined analysis of these two studies showed ACIPHEX 20 mg significantly improved other GERD-associated symptoms (regurgitation, belching and early satiety) by week 4 compared with placebo (all p values < 0.005).

ACIPHEX 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

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:

At Weeks 2 and 4, significantly more patients in the ACIPHEX 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p<=0.018), daytime pain severity (p<=0.023), and nighttime pain severity (p<=0.035) compared with placebo patients. The only exception was the ACIPHEX 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both ACIPHEX groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both ACIPHEX groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg ACIPHEX QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between ACIPHEX and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, ACIPHEX was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

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 Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

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.

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.

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.

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 25degC (77degF); excursions permitted to 15-30degC (59-86degF) [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 62856-240-30)

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 62856-241-30)

Store at 25degC (77degF); excursions permitted to 15-30degC (59-86degF) [see USP Controlled Room Temperature]. Protect from moisture.

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. apple sauce, 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 (5.3)].

MEDICATION GUIDE

ACIPHEX(r) (a-se-feks) (rabeprazole sodium) Delayed-Release Tablets

ACIPHEX(R) Sprinkle(tm) (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.

• 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 about all of your medical conditions, including 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.

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

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: Take the dose 30 minutes before a meal. Open the capsule and sprinkle the contents onto a small amount of soft food such as apple sauce, 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(r). The food or liquid that you use should be at or below room temperature. Swallow the entire mixture. Do not chew or crush the granules. 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.

• Take the dose 30 minutes before a meal.

• Open the capsule and sprinkle the contents onto a small amount of soft food such as apple sauce, 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 (r) . The food or liquid that you use should be at or below room temperature.

• Swallow the entire mixture. Do not chew or crush the granules.

• 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 can cause serious side effects, including:

• See "What is the most important information I should know about ACIPHEX?"

• 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.

• 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

The most common side effects with ACIPHEX may include:

• headache

• pain

• sore throat

• 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 have 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 77degF (20degC to 25degC).

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.

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.

Distributed by Eisai Inc., Woodcliff Lake, NJ 07677Marketed by Janssen Pharmaceuticals Inc., Titusville, NJ 08560

Revised March 2013

ACIPHEX(r) is a registered trademark of Eisai R&D Management Co., Ltd; ACIPHEX(r) Sprinkle(tm) 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.

PRINCIPAL DISPLAY PANEL - 20 MG DELAYED-RELEASE TABLET

NDC 62856-243-30

Rx only

AcipHex(r) rabeprazole sodiumdelayed-releasetablets

20 mg30 tablets

PRINCIPAL DISPLAY PANEL - 5 MG DELAYED-RELEASE CAPSULE

NDC 62856-240-30

Rx only

AcipHex(r) (rabeprazole sodium)delayed-releaseSprinkle Capsules

5 mg30 capsules

PRINCIPAL DISPLAY PANEL - 10 MG DELAYED-RELEASE CAPSULE

NDC 62856-241-30

Rx only

AcipHex(r) (rabeprazole sodium)delayed-releaseSprinkle Capsules

10 mg30 capsules