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Aciphex (Rabeprazole) in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate . Eradication of has been shown to reduce the risk of duodenal ulcer recurrence. {See () and ()}

In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. {See () and the clarithromycin package insert, }

Aciphex (Rabeprazole) tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Aciphex (Rabeprazole) can be taken with or without food.

20 mg light yellow enteric-coated delayed release tablets. The name and strength, in mg, (Aciphex (Rabeprazole) 20) is imprinted on one side.

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CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE.
WARNINGS
Amoxicillin
There have been well-documented reports of individuals with a history of penicillin hypersensitivity reactions that have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporin, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted. (See in prescribing information for amoxicillin.)

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by is a primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluid and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against

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 infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with 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.

Worldwide, over 2900 patients have been treated with rabeprazole in Phase II-III clinical trials involving various dosages and durations of treatment.

Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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In vitro

50
max
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 C 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.

Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.{See ()}.

Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. (See in prescribing information for clarithromycin.) (See in prescribing information for amoxicillin.)

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Teratogenic Effects. Pregnancy Category B:

Use of Aciphex (Rabeprazole) in adolescent patients 12 years of age and above for short-term treatment of GERD is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of Aciphex (Rabeprazole) for adults {see (, , ) and (, , )};b) safety and pharmacokinetic studies performed in adolescent patients {see ()}. The safety and effectiveness of Aciphex (Rabeprazole) for the treatment of GERD patients
In a multicenter, randomized, open-label, parallel-group study, 111 adolescents 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 (Rabeprazole) 10 mg or Aciphex (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 events 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.

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.

The active ingredient in Aciphex (Rabeprazole) Delayed-Release Tablets is rabeprazole sodium, a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1benzimidazole sodium salt. It has an empirical formula of CHNNaOS and a molecular weight of 381.43. 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 formula is:

Aciphex (Rabeprazole) is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium.

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.

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Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H, KATPase 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 , 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.

Antisecretory Activity
The anti-secretory effect begins within one hour after oral administration of 20 mg Aciphex (Rabeprazole) . The median inhibitory effect of Aciphex (Rabeprazole) on 24 hour gastric acidity is 88% of maximal after the first dose. Aciphex (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, KATPase.

*(p
Compared to placebo, Aciphex (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.

*(p
After administration of 20 mg Aciphex (Rabeprazole) 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 (Rabeprazole) 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 (Rabeprazole) 20 mg and 40 mg per day decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that esophageal pH4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving Aciphex (Rabeprazole) 20 mg and in 100% of subjects receiving Aciphex (Rabeprazole) 40 mg. With Aciphex (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 Aciphex (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 (Rabeprazole) 20 mg 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 , ()}.

In over 400 patients treated with Aciphex (Rabeprazole) (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 (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 Aciphex (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 Aciphex (Rabeprazole) and ocular effects.

Microbiology
The following 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 in vitro and in clinical infections as described in the () and ()sections.

Helicobacter pylori
Susceptibility testing of isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

a
Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates
Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes:
Patients with persistent 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.

Aciphex (Rabeprazole) delayed-release tablets 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 (Rabeprazole) , peak plasma concentrations (C) of rabeprazole occur over a range of 2.0 to 5.0 hours (T). The rabeprazole Cand 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 are not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

Absorption
Distribution
Elimination
14
max
Pediatric
Gender and Race
0-∞
2
Hepatic Disease
0-24
In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC and C 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 section () for information on dosage adjustment in patients with hepatic impairment.

Combined Administration with Antimicrobials

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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 (Rabeprazole) 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:

*(p
In addition, there was a statistically significant difference in favor of the Aciphex (Rabeprazole) 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p0.026). All Aciphex (Rabeprazole) groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all Aciphex (Rabeprazole) groups when compared to placebo at both Weeks 4 and 8 (p0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, Aciphex (Rabeprazole) 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):

*(p
Aciphex (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
Two U.S., multicenter, double-blind, placebo controlled studies were conducted in 316 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 (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 Aciphex (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.

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 (Rabeprazole) 20mg significantly improved other GERD-associated symptoms (regurgitation, belching and early satiety) by week 4 compared with placebo (all p values
Aciphex (Rabeprazole) 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p
In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Aciphex (Rabeprazole) QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Aciphex (Rabeprazole) was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

*p0.001 versus placebo

At Weeks 2 and 4, significantly more patients in the Aciphex (Rabeprazole) 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p0.018), daytime pain severity (p0.023), and nighttime pain severity (p0.035) compared with placebo patients. The only exception was the Aciphex (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 Aciphex (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 Aciphex (Rabeprazole) groups compared to placebo at Weeks 2 and 4 (p
An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg Aciphex (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 Aciphex (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, Aciphex (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:

Aciphex (Rabeprazole) and omeprazole were comparable in providing complete resolution of symptoms.

1. National Committee for Clinical Laboratory Standards. —Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.

Aciphex (Rabeprazole) 20 mg is supplied as delayed-release light yellow enteric-coated tablets. The name and strength, in mg, (Aciphex (Rabeprazole) 20) is imprinted on one side.

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

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Read the Patient Information that comes with Aciphex (Rabeprazole) before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

Aciphex (Rabeprazole) is a medicine called a proton pump inhibitor or an "acid pump inhibitor". This means it reduces the amount of acid that is made by your stomach. Aciphex (Rabeprazole) is used in adults:

Aciphex (Rabeprazole) is used in adolescents 12 years of age and above:

The most common side effects with Aciphex (Rabeprazole) may include:

These are not all the side effects of Aciphex (Rabeprazole) . For more information, ask your doctor or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Aciphex (Rabeprazole) for any condition for which it was not prescribed by your doctor. Do not give Aciphex (Rabeprazole) to other people, even if they have the same symptoms as you. It may harm them.

This leaflet summarizes the most important information about Aciphex (Rabeprazole) . If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Aciphex (Rabeprazole) that is written for healthcare professionals. For full product information, visit the website at or call the toll free number 1-888-4-Aciphex (Rabeprazole) or 1-800 JANSSEN.

Active Ingredient: rabeprazole sodium

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.

The following are registered trademarks of their respective manufacturers:

Reyataz (Bristol-Myers Squibb Company), Sandimmune and Neoral (Novartis Pharmaceuticals Corporation), Lanoxin (GlaxoSmithKline), Nizoral (Janssen Pharmaceutica Products, LP), and Coumadin (Bristol-Myers Squibb Company).

Your stomach needs acid to help your body digest food. Stomach acid is made by tiny acid pumps in the cells that line your stomach. If your body makes too much acid or cannot protect itself against a normal amount of acid, medical problems such as GERD can happen.

GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. Stomach acid can damage (erode) the lining of your esophagus. Some symptoms of GERD are heartburn, sour taste in the back of your throat and burping.

For prescription only

Revised June 2008

Aciphex (Rabeprazole) is a registered trademark of Eisai Co., Ltd., Tokyo, Japan.

Manufactured and Marketed by Eisai Inc., Woodcliff Lake, NJ 06766Marketed by PRICARA, Unit of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ 08869

Aciphex (Rabeprazole) 20 mg