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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 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.
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 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 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.
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
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rabeprazole in adult patients.
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 ACIPHEX patients (n=1064), and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions:
pain (3% vs. 1%)
pharyngitis (3% vs. 2%)
flatulence (3% vs. 1%)
infection (2% vs. 1%)
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 [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].
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.
