Rabeprazole

Rabeprazole
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]

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Overview

Rabeprazole is a proton-pump inhibitor (PPI) that is FDA approved for the treatment of Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers, Helicobacter pylori Eradication, Pathological Hypersecretory Conditions including Zollinger-Ellison Syndrome. Common adverse reactions include abdominal pain, headache, diarrhoea, nausea, vomiting, flatulence, infection and constipation.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• Healing of Erosive or Ulcerative GERD in Adults

• Rabeprazole 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 Rabeprazole may be considered.

• Maintenance of Healing of Erosive or Ulcerative GERD in Adults

• Rabeprazole 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.

• Treatment of Symptomatic GERD in Adults

• Rabeprazole is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks.

• Healing of Duodenal Ulcers in Adults

• Rabeprazole 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.

• Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults

• Rabeprazole, 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.
• 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

• Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults

• Rabeprazole is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

• Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older

• Rabeprazole is indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.

Dosage

• Healing of Erosive or Ulcerative GERD in Adults

• The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily for four to eight weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole may be considered.

• Maintenance of Healing of Erosive or Ulcerative GERD in Adults

• The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily. Controlled studies do not extend beyond 12 months.

• Treatment of Symptomatic GERD in Adults

• The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily for 4 weeks. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered.

• Healing of Duodenal Ulcers in Adults

The recommended adult oral dose is one Rabeprazole 20 mg Delayed-Release tablet to be taken once daily after the morning meal for a period up to four weeks. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.

• Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults

• 

• Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults

• The dosage of Rabeprazole 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 Rabeprazole for up to one year.

• 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

• 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.

Dosage forms and strengths

• Delayed-Release Tablets: 20 mg
• Delayed-Release Capsules: 5 mg and 10 mg

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Rabeprazole in adult patients.

Non–Guideline-Supported Use

• Gastric ulcer
• Helicobacter pylori gastrointestinal tract infection - Peptic ulcer disease, Quadruple therapy
• Indigestion
• Laryngopharyngeal reflux

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Indications

• Treatment of GERD in Pediatric Patients 1 to 11 Years of Age

• Rabeprazole is indicated for treatment of GERD in children 1 to 11 years of age for up to 12 weeks.

Dosage

• Treatment of GERD in Pediatric Patients 1 to 11 Years of Age

• The recommended dosage of Rabeprazole 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.
• 15 kg or more: 10 mg once daily for up to 12 weeks

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Rabeprazole in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Rabeprazole in pediatric patients.

Contraindications

• Rabeprazole 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

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.

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.

Acute Interstitial Nephritis

• Acute interstitial nephritis has been observed in patients taking PPIs including Rabeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue Rabeprazole if acute interstitial nephritis develops.

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.

Clostridium difficile Associated Diarrhea

• Published observational studies suggest that PPI therapy like Rabeprazole 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.
• 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.

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.

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.

Concomitant Use of Rabeprazole 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

Adverse Reactions

Clinical Trials Experience

Clinical Studies Experience

Adults

• The data described below reflect exposure to Rabeprazole in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled 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 Rabeprazole.
• An analysis of adverse reactions appearing in ≥2% of Rabeprazole 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%)
• 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 while 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 Rabeprazole, 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
• 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 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.

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%)
• abdominal pain (3.6%)

• The related reported adverse reactions that occurred in ≥2% of patients were:

• headache (5.4%)
• 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%)
• headache (5%)

Postmarketing Experience

• The following adverse reactions have been identified during post approval use of Rabeprazole. 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
• delirium
• anaphylaxis
• angioedema
• bullous and other drug eruptions of the skin
• severe dermatologic reactions, including toxic epidermal necrolysis (some fatal)
• Stevens-Johnson syndrome
• erythema multiforme
• interstitial pneumonia
• interstitial nephritis
• TSH elevations
• bone fractures
• hypomagnesemia
• Clostridium difficile associated diarrhea
• agranulocytosis
• hemolytic anemia
• leukopenia
• pancytopenia
• thrombocytopenia

• Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.

Drug Interactions

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.

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.

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.

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 Rabeprazole.
• 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. Co-administration 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.

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.

Combined Administration with Clarithromycin

Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.

• Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs

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.

Clopidogrel

• Concomitant administration of rabeprazole and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Rabeprazole.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

Risk Summary

• There are no adequate and well-controlled studies with Rabeprazole 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. Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation. Because of these findings, Rabeprazole 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 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rabeprazole in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Rabeprazole during labor and delivery.

Nursing Mothers

• It is not known if Rabeprazole is excreted in human milk; however, rabeprazole is present in rat milk. Because many drugs are excreted in milk, caution should be exercised when Rabeprazole is administered to a nursing woman.

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 Rabeprazole 10 mg or Rabeprazole 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 Rabeprazole 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 Rabeprazole 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 Rabeprazole 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 Rabeprazole.
• 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 Rabeprazole 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 Rabeprazole.

Geriatic Use

• Of the total number of subjects in clinical studies of Rabeprazole, 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.

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.

Race

There is no FDA guidance on the use of Rabeprazole with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Rabeprazole in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Rabeprazole in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Rabeprazole in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Rabeprazole in patients who are immunocompromised.

Administration and Monitoring

Administration

• 

Monitoring

• Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
• 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.

IV Compatibility

There is limited information regarding IV Compatibility of Rabeprazole in the drug label.

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.

Pharmacology

1 : 1 mixture (racemate)Rabeprazole
Systematic (IUPAC) name
(RS)-2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole
Identifiers
CAS number	117976-89-3
ATC code	A02BC04
PubChem	5029
DrugBank	DB01129
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	359.444 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	52%
Metabolism	mostly non-enzymatic, partly hepatic (CYP2C19)
Half life	1 - 1.5 hours
Excretion	90% renal
Therapeutic considerations
Licence data	Finix&SearchType=BasicSearch US
Pregnancy cat.	B(US)
Legal status	POM(UK) [[Prescription drug|Template:Unicode-only]](US)
Routes	Oral

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.

Structure

• 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:

This image is provided by the National Library of Medicine.

Pharmacodynamics

Antisecretory Activity

• The antisecretory effect begins within one hour after oral administration of 20 mg Rabeprazole. The median inhibitory effect of Rabeprazole on 24-hour gastric acidity is 88% of maximal after the first dose. Rabeprazole 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, Rabeprazole, 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 Rabeprazole 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 Rabeprazole 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, Rabeprazole 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 Rabeprazole 20 mg and in 100% of subjects receiving Rabeprazole 40 mg. With Rabeprazole 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 Rabeprazole 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.
• In over 400 patients treated with Rabeprazole 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 Rabeprazole for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-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 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.

Other Effects

• In humans treated with Rabeprazole 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 Rabeprazole 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.

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

• larithromycin pretreatment resistance rate (MIC ≥1 μg/mL) to H. pylori was 9% (51/ 560) at baseline in all treatment groups combined. A total of >99% (558/560) of patients had H. pylori isolates, which were considered to be susceptible (MIC ≤0.25 μg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL.
• For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

• 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.

Pharmacokinetics

• Rabeprazole 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 Rabeprazole 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 Rabeprazole 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 Rabeprazole Tablets may be taken without regard to timing of meals.
• After oral administration to healthy adults of 10 mg Rabeprazole 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 (15 mL) 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.

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 Rabeprazole Tablets in adolescents and adults.

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.

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 Rabeprazole 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 Rabeprazole was coadministered compared to administration of clopidogrel with placebo.

Nonclinical Toxicology

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 AUC0-∞ = 0.88 μg•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 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.

Animal Toxicology and/or Pharmacology

• Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25, or 150 mg/kg/day and dogs were dosed at 3, 10, or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.
• When juvenile animals were treated for 28 days with a different PPI at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed.

Clinical Studies

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 Rabeprazole 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 Rabeprazole 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 Rabeprazole 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, Rabeprazole was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment:

• Rabeprazole 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). Rabeprazole 20 mg once daily was also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

Long-term Maintenance of Healing of Erosive or Ulcerative GERD in Adults

• The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S. multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of Rabeprazole QD or placebo. As demonstrated in the tables below, Rabeprazole 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:

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 Rabeprazole 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 Rabeprazole 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.

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

Healing of Duodenal Ulcers in Adults

• In a U.S. randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Rabeprazole QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole 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 Rabeprazole 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 Rabeprazole 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 Rabeprazole 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 Rabeprazole 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 Rabeprazole 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, Rabeprazole 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:

• Rabeprazole and omeprazole were comparable in providing complete resolution of symptoms.

Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease in Adults

• The U.S. multicenter study was a double-blind, parallel-group comparison of rabeprazole, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin, and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults

• Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with Rabeprazole at doses from 20 to 120 mg for up to 12 months. Rabeprazole produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Rabeprazole also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of Rabeprazole used to treat this small cohort of patients with gastric hypersecretion were well tolerated.

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 Rabeprazole 10 mg or Rabeprazole 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.

How Supplied

• Rabeprazole 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)

Storage

• Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.

Images

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Package and Label Display Panel

PRINCIPAL DISPLAY PANEL - 20 MG DELAYED-RELEASE TABLET

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Patient Counseling Information

How to Take Rabeprazole

• Patients should be cautioned that Rabeprazole Delayed-Release Tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Rabeprazole can be taken with or without food.
• Rabeprazole 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

Precautions with Alcohol

• Alcohol-Rabeprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Aciphex

Look-Alike Drug Names

There is limited information regarding Rabeprazole Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.