These Highlights Do Not Include All The Information Needed To Use Rabeprazole Sodium Delayed-release Tablets Safely And Effectively. See Full Prescribing Information For Rabeprazole Sodium Delayed-release Tablets.

Pregnancy Category B

Adults

The data described below reflect exposure to Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets.

An analysis of adverse reactions appearing in ³ 2% of Rabeprazole Sodium Delayed-Release Tablet patients (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).

Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to rabeprazole for 6 months 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 Sodium Delayed-Release Tablets, 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 that were seen in controlled clinical trials, which do not meet the above criteria (≥ 2% of Rabeprazole Sodium Delayed-Release Tablets treated patients and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.

MEDICATION GUIDE

Rabeprazole Sodium Delayed-Release Tablets

CIA76375B

Rev. 2E 10/2013

Read the Medication Guide that comes with Rabeprazole Sodium Delayed-Release Tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about Rabeprazole Sodium Delayed-Release Tablets?

Rabeprazole Sodium Delayed-Release Tablets may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Rabeprazole Sodium Delayed-Release Tablets can cause serious side effects, including:

• •
  Diarrhea. Rabeprazole Sodium Delayed-Release Tablets may increase your risk of getting severe diarrhea. This diarrhea may be caused by in an infection (Clostridium difficile) in your intestines.
  
  Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.
• •
  Bone fractures. People who take multiple daily doses of Proton Pump Inhibitor medicines for a long period of time (1 year or longer) may have an increased risk of fractures of the hip, wrist, or spine. You should take Rabeprazole Sodium Delayed-Release Tablets exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take Rabeprazole Sodium Delayed-Release Tablets.
  
  Rabeprazole Sodium Delayed-Release Tablets can have other serious side effects. See "What are the possible side effects of Rabeprazole Sodium Delayed-Release Tablets?"

What is Rabeprazole Sodium Delayed-Release Tablets?

Rabeprazole Sodium Delayed-Release Tablet is a prescription medicine called a proton pump inhibitor (PPI). Rabeprazole Sodium Delayed-Release Tablets reduces the amount of acid in your stomach.

Rabeprazole Sodium Delayed-Release Tablets is used in adults:

• •
  for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) and to relieve symptoms, such as heartburn pain. If needed, your doctor may decide to prescribe another 8 weeks of Rabeprazole Sodium Delayed-Release Tablets.
• •
  to maintain the healing of the esophagus and relief of symptoms related to EE. It is not known if Rabeprazole Sodium Delayed-Release Tablets is safe and effective if used longer than 12 months (1 year).
• •
  for 4 weeks to treat daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD).
  
  GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.
• •
  for up to 4 weeks for the healing and relief of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
• •
  for 7 days with certain antibiotic medicines to treat an infection caused by bacteria called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back.
• •
  for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison syndrome.
  
  Rabeprazole Sodium Delayed-Release Tablets is used in adolescents 12 years of age and older:
• •
  for up to 8 weeks to treat daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD).

It is not known if Rabeprazole Sodium Delayed-Release Tablets is safe and effective in children under the age of 12.

Who should not take Rabeprazole Sodium Delayed-Release Tablets?

Do not take Rabeprazole Sodium Delayed-Release Tablets if you:

• •
  are allergic to rabeprazole or any of the other ingredients in Rabeprazole Sodium Delayed-Release Tablets. See the end of this Medication Guide for a complete list of ingredients in Rabeprazole Sodium Delayed-Release Tablets.
• •
  are allergic to any other Proton Pump Inhibitor (PPI) medicine.

What should I tell my doctor before taking Rabeprazole Sodium Delayed-Release Tablets?

Before you take Rabeprazole Sodium Delayed-Release Tablets tell your doctor if you:

• •
  have been told that you have low magnesium levels in your blood.
• •
  have liver problems.
• •
  have any allergies.
• •
  have any other medical conditions.
• •
  are pregnant or planning to become pregnant. It is not known if Rabeprazole Sodium Delayed-Release Tablets can harm your unborn baby.
• •
  are breastfeeding. It is not known if Rabeprazole Sodium Delayed-Release Tablets passes into your breast milk. You and your doctor should decide if you will take Rabeprazole Sodium Delayed-Release Tablets or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take Rabeprazole Sodium Delayed-Release Tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Rabeprazole Sodium Delayed-Release Tablets may affect how other medicines work, and other medicines may affect how Rabeprazole Sodium Delayed-Release Tablets works.

Especially tell your doctor if you take:

• •
  atazanavir (Reyataz)
• •
  cyclosporine (Sandimmune, Neoral)
• •
  digoxin (Lanoxin)
• •
  ketoconazole (Nizoral)
• •
  warfarin (Coumadin)
• •
  theophylline (THEO-24 Thelair)
• •
  diazepam (Valium)
• •
  phenytoin (Dilantin)
• •
  an antibiotic that contains amoxicillin or clarithromycin
• •
  a "water pill" (diuretic)
• •
  methotrexate

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Rabeprazole Sodium Delayed-Release Tablets?

• •
  Take Rabeprazole Sodium Delayed-Release Tablets exactly as prescribed. Your doctor will prescribe the dose that is right for you and your medical condition. Do not change your dose or stop taking Rabeprazole Sodium Delayed-Release Tablets unless you talk to your doctor. Take Rabeprazole Sodium Delayed-Release Tablets for as long as it is prescribed even if you feel better.
• •
  Rabeprazole Sodium Delayed-Release Tablets is usually taken one time each day. Your doctor will tell you the time of day to take Rabeprazole Sodium Delayed-Release Tablets, based on your medical condition.
• •
  Rabeprazole Sodium Delayed-Release Tablets can be taken with or without food. Your doctor will tell you whether to take this medicine with or without food based on your medical condition.
• •
  Swallow each Rabeprazole Sodium Delayed-Release Tablet whole with water. Do not chew, crush, or split Rabeprazole Sodium Delayed-Release Tablets. Tell your doctor if you cannot swallow tablets whole. You may need a different medicine.
• •
  If you miss a dose of Rabeprazole Sodium Delayed-Release Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• •
  If you take too much Rabeprazole Sodium Delayed-Release Tablets, call your doctor or Poison Control Center right away, or go to the nearest hospital emergency room.
• •
  Your doctor may prescribe antibiotic medicines with Rabeprazole Sodium Delayed-Release Tablets to help treat a stomach infection and heal stomach (duodenal) ulcers that are caused by bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it.

What are the possible side effects of Rabeprazole Sodium Delayed-Release Tablets?

Rabeprazole Sodium Delayed-Release Tablets can cause serious side effects including:

• •
  See "What is the most important information I should know about Rabebprazole Sodium Delayed-Release Tablets?"
• •
  Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.
  
  
  
  Tell your doctor right away if you have any of these symptoms:
  • o
    seizures
  • o
    dizziness
  • o
    abnormal or fast heart beat
  • o
    jitteriness
  • o
    jerking movements or shaking (tremors)
  • o
    muscle weakness
  • o
    spasms of the hands and feet
  • o
    cramps or muscle aches
  • o
    spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking Rabeprazole Sodium Delayed-Release Tablets, during treatment, or if you will be taking Rabeprazole Sodium Delayed-Release Tablets for a long period of time.

The most common side effects with Rabeprazole Sodium Delayed-Release Tablets include:

• •
  headache
• •
  pain
• •
  sore throat
• •
  gas
• •
  infection
• •
  constipation

Other side effects:

• •
  Serious allergic reactions. Tell your doctor if you have any of the following symptoms with Rabeprazole Sodium Delayed-Release Tablets.
• •
  rash
• •
  face swelling
• •
  throat tightness
• •
  difficulty breathing

Your doctor may stop Rabeprazole Sodium Delayed-Release Tablets if these symptoms happen.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of Rabeprazole Sodium Delayed-Release Tablets. For more information, ask your doctor or pharmacist.

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

How should I store Rabeprazole Sodium Delayed-Release Tablets?

• •
  Store Rabeprazole Sodium Delayed-Release Tablets in a dry place at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Rabeprazole Sodium Delayed-Release Tablets and all medicines out of the reach of children.

General Information about Rabeprazole Sodium Delayed-Release Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Rabeprazole Sodium Delayed-Release Tablets for a condition for which it was not prescribed. Do not give Rabeprazole Sodium Delayed-Release Tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Rabeprazole Sodium Delayed-Release Tablets. If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Rabeprazole Sodium Delayed-Release Tablets that is written for healthcare professionals. For more information, go to http://www.kremersurban.com/ or call 1-866-822-0068.

What are the ingredients in Rabeprazole Sodium Delayed-Release Tablets?

Active Ingredient: rabeprazole sodium

Inactive Ingredients: crospovidone, FD&C Blue #1, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, talc and triethyl citrate.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Kremers Urban Pharmaceuticals Inc.

Princeton, NJ 08540, USA

Repackaged and Relabeled by:

Proficient Rx LP

Thousand Oaks, CA 91320

CIA76375B

Rev. 2E 10/2013

All brand names are the trademarks of their respective owners.

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

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.

There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2) ].

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.

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.

The active ingredient in Rabeprazole Sodium Delayed-Release Tablets 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 formula is:

Rabeprazole Sodium Delayed-Release Tablets 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 crospovidone, FD&C Blue #1, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, talc and triethyl citrate.

Concomitant administration of rabeprazole and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel [see Clinical Pharmacology (12.3) ]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Rabeprazole Sodium Delayed-Release Tablets.

In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC₅₀ of 62 micromolar, a concentration that is over 50 times higher than the C_max in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.6) ].

Several published observational studies in adults suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.2) ].

Of the total number of subjects in clinical studies of Rabeprazole Sodium Delayed-Release Tablets, 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.

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ].

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

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with Rabeprazole Sodium Delayed-Release Tablets, refer to the Contraindications section of their package inserts.

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.

• •
  Increased INR and prothrombin times have been reported with concomitant use with warfarin. Patients need to be monitored (7.2)
• •
  Rabeprazole has been shown to inhibit cyclosporine metabolism in vitro (7.3)
• •
  Rabeprazole Sodium Delayed-Release Tablets inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, iron salts and digoxin) (7.4)
• •
  Rabeprazole Sodium Delayed-Release Tablets may reduce the plasma levels of atazanavir (7.4)
• •
  Methotrexate: Rabeprazole Sodium Delayed-Release Tablets may increase serum level of methotrexate (7.7)

It is not known if Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets is administered to a nursing woman.

Rabeprazole Sodium 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 Rabeprazole Sodium Delayed-Release Tablets, peak plasma concentrations (C_max) of rabeprazole occur over a range of 2 to 5 hours (T_max). The rabeprazole C_max 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.

Rabeprazole Sodium Delayed-Release Tablets is a proton pump inhibitor (PPI) indicated in adults for:

• •
  Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)(1.1)
• •
  Maintenance of Healing of Erosive or Ulcerative GERD (1.2)
• •
  Treatment of Symptomatic GERD (1.3)
• •
  Healing of Duodenal Ulcers (1.4)
• •
  Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (1.5)
• •
  Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (1.6)

In adolescent patients 12 years of age and older for:

• •
  Short-term treatment of Symptomatic GERD (1.7)

Rabeprazole Sodium Delayed-Release Tablets in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.5) and Dosage and Administration (2.5) ].

In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see Clinical Pharmacology (12.2) and the clarithromycin package insert, Clinical Pharmacology (12.2) ].

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.

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.

Published observational studies suggest that PPI therapy like Rabeprazole Sodium Delayed-Release Tablets may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with Rabeprazole Sodium Delayed-Release Tablets, refer to Warnings and Precautions sections of those package inserts.

• •
  Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy (5.1)
• •
  Use with warfarin: monitor for increases in INR and prothrombin time (5.2)
• •
  PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea (5.3)
• •
  Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (5.4)
• •
  Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.5)

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

Rabeprazole Sodium Delayed-Release Tablets are provided in strength of 20 mg.

The following adverse reactions have been identified during post approval use of Rabeprazole Sodium Delayed-Release Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sudden death; coma, hyperammonemia; jaundice; rhabdomyolysis; disorientation and delirium; anaphylaxis; angioedema; bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; interstitial pneumonia; interstitial nephritis; TSH elevations, bone fractures, hypomagnesemia and Clostridium difficile associated diarrhea. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported. Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.

• •
  The safety and efficacy of Rabeprazole Sodium Delayed-Release Tablets for GERD have not been established for pediatric patients less than 12 years of age (8.4).
• •
  The safety and efficacy of Rabeprazole Sodium Delayed-Release Tablets for the other adult indications have not been established for pediatric patients (8.4).

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.

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.

See FDA-approved patient labeling (Error! Hyperlink reference not valid.).

How to Take Rabeprazole Sodium Delayed-Release Tablets

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

Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.3) ].

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.

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.

Rabeprazole Sodium Delayed-Release Tablets 20 mg is supplied as delayed-release blue enteric-coated round tablets debossed with "KU" on one side and "7" on the other.

Rabeprazole Sodium Delayed-Release Tablets 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.

The recommended adult oral dose is one Rabeprazole Sodium 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 (1.4) ]. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.

In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Rabeprazole Sodium Delayed-Release Tablets QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole Sodium Delayed-Release Tablets 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 Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets and omeprazole were comparable in providing complete resolution of symptoms.

Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 postpartum and followed by a 13-week recovery period. Rats were dosed at 5, 25 or 150 mg/kg/day and dogs were dosed at 3, 10 or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.

Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults.

The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for 4 weeks [see Indications and Usage (1.3) ]. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. The recommended adolescent dosing is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for 8 weeks.

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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

Rabeprazole Sodium

Delayed-Release

Tablets

20 mg

Rx Only

PHARMACIST: Dispense the

accompanying Medication Guide

to each patient.

Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.3) ].

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin] [see Drug Interactions in prescribing information for amoxicillin].

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.

Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets may be considered.

The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for four to eight weeks [see Indications and Usage (1.1) ]. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole Sodium Delayed-Release Tablets may be considered.

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 Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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):

Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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.

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_max 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.

In a 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 µg∙hr/mL which is 1.6 times the human exposure (plasma AUC_0-∞ = 0.88 µg∙hr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week carcinogenicity study in p53^+/- transgenic mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17-24 times the human exposure at the recommended dose for GERD. In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30 and 60 mg/kg/day and females with 5, 15, 30, 60 and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 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.

Rabeprazole Sodium Delayed-Release Tablets 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.

The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily [see Indications and Usage (1.2) ].

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 Sodium Delayed-Release Tablets QD or placebo. As demonstrated in the tables below, Rabeprazole Sodium Delayed-Release Tablets 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:

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7.7) ].

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

Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.

The recommended oral dose for adolescents 12 years of age and older is one 20 mg Delayed-Release Tablet once daily for up to 8 weeks [see Use in Specific Populations (8.4) and Clinical Studies (14.7) ].

Rabeprazole Sodium Delayed-Release Tablets is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

The dosage of Rabeprazole Sodium Delayed-Release Tablets in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. 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 Sodium Delayed-Release Tablets for up to one year.

Pregnancy Category B

Adults

The data described below reflect exposure to Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets.

An analysis of adverse reactions appearing in ³ 2% of Rabeprazole Sodium Delayed-Release Tablet patients (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).

Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to rabeprazole for 6 months 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 Sodium Delayed-Release Tablets, 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 that were seen in controlled clinical trials, which do not meet the above criteria (≥ 2% of Rabeprazole Sodium Delayed-Release Tablets treated patients and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.

MEDICATION GUIDE

Rabeprazole Sodium Delayed-Release Tablets

CIA76375B

Rev. 2E 10/2013

Read the Medication Guide that comes with Rabeprazole Sodium Delayed-Release Tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about Rabeprazole Sodium Delayed-Release Tablets?

Rabeprazole Sodium Delayed-Release Tablets may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Rabeprazole Sodium Delayed-Release Tablets can cause serious side effects, including:

• •
  Diarrhea. Rabeprazole Sodium Delayed-Release Tablets may increase your risk of getting severe diarrhea. This diarrhea may be caused by in an infection (Clostridium difficile) in your intestines.
  
  Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.
• •
  Bone fractures. People who take multiple daily doses of Proton Pump Inhibitor medicines for a long period of time (1 year or longer) may have an increased risk of fractures of the hip, wrist, or spine. You should take Rabeprazole Sodium Delayed-Release Tablets exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take Rabeprazole Sodium Delayed-Release Tablets.
  
  Rabeprazole Sodium Delayed-Release Tablets can have other serious side effects. See "What are the possible side effects of Rabeprazole Sodium Delayed-Release Tablets?"

What is Rabeprazole Sodium Delayed-Release Tablets?

Rabeprazole Sodium Delayed-Release Tablet is a prescription medicine called a proton pump inhibitor (PPI). Rabeprazole Sodium Delayed-Release Tablets reduces the amount of acid in your stomach.

Rabeprazole Sodium Delayed-Release Tablets is used in adults:

• •
  for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) and to relieve symptoms, such as heartburn pain. If needed, your doctor may decide to prescribe another 8 weeks of Rabeprazole Sodium Delayed-Release Tablets.
• •
  to maintain the healing of the esophagus and relief of symptoms related to EE. It is not known if Rabeprazole Sodium Delayed-Release Tablets is safe and effective if used longer than 12 months (1 year).
• •
  for 4 weeks to treat daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD).
  
  GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.
• •
  for up to 4 weeks for the healing and relief of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
• •
  for 7 days with certain antibiotic medicines to treat an infection caused by bacteria called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back.
• •
  for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison syndrome.
  
  Rabeprazole Sodium Delayed-Release Tablets is used in adolescents 12 years of age and older:
• •
  for up to 8 weeks to treat daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD).

It is not known if Rabeprazole Sodium Delayed-Release Tablets is safe and effective in children under the age of 12.

Who should not take Rabeprazole Sodium Delayed-Release Tablets?

Do not take Rabeprazole Sodium Delayed-Release Tablets if you:

• •
  are allergic to rabeprazole or any of the other ingredients in Rabeprazole Sodium Delayed-Release Tablets. See the end of this Medication Guide for a complete list of ingredients in Rabeprazole Sodium Delayed-Release Tablets.
• •
  are allergic to any other Proton Pump Inhibitor (PPI) medicine.

What should I tell my doctor before taking Rabeprazole Sodium Delayed-Release Tablets?

Before you take Rabeprazole Sodium Delayed-Release Tablets tell your doctor if you:

• •
  have been told that you have low magnesium levels in your blood.
• •
  have liver problems.
• •
  have any allergies.
• •
  have any other medical conditions.
• •
  are pregnant or planning to become pregnant. It is not known if Rabeprazole Sodium Delayed-Release Tablets can harm your unborn baby.
• •
  are breastfeeding. It is not known if Rabeprazole Sodium Delayed-Release Tablets passes into your breast milk. You and your doctor should decide if you will take Rabeprazole Sodium Delayed-Release Tablets or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take Rabeprazole Sodium Delayed-Release Tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Rabeprazole Sodium Delayed-Release Tablets may affect how other medicines work, and other medicines may affect how Rabeprazole Sodium Delayed-Release Tablets works.

Especially tell your doctor if you take:

• •
  atazanavir (Reyataz)
• •
  cyclosporine (Sandimmune, Neoral)
• •
  digoxin (Lanoxin)
• •
  ketoconazole (Nizoral)
• •
  warfarin (Coumadin)
• •
  theophylline (THEO-24 Thelair)
• •
  diazepam (Valium)
• •
  phenytoin (Dilantin)
• •
  an antibiotic that contains amoxicillin or clarithromycin
• •
  a "water pill" (diuretic)
• •
  methotrexate

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Rabeprazole Sodium Delayed-Release Tablets?

• •
  Take Rabeprazole Sodium Delayed-Release Tablets exactly as prescribed. Your doctor will prescribe the dose that is right for you and your medical condition. Do not change your dose or stop taking Rabeprazole Sodium Delayed-Release Tablets unless you talk to your doctor. Take Rabeprazole Sodium Delayed-Release Tablets for as long as it is prescribed even if you feel better.
• •
  Rabeprazole Sodium Delayed-Release Tablets is usually taken one time each day. Your doctor will tell you the time of day to take Rabeprazole Sodium Delayed-Release Tablets, based on your medical condition.
• •
  Rabeprazole Sodium Delayed-Release Tablets can be taken with or without food. Your doctor will tell you whether to take this medicine with or without food based on your medical condition.
• •
  Swallow each Rabeprazole Sodium Delayed-Release Tablet whole with water. Do not chew, crush, or split Rabeprazole Sodium Delayed-Release Tablets. Tell your doctor if you cannot swallow tablets whole. You may need a different medicine.
• •
  If you miss a dose of Rabeprazole Sodium Delayed-Release Tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• •
  If you take too much Rabeprazole Sodium Delayed-Release Tablets, call your doctor or Poison Control Center right away, or go to the nearest hospital emergency room.
• •
  Your doctor may prescribe antibiotic medicines with Rabeprazole Sodium Delayed-Release Tablets to help treat a stomach infection and heal stomach (duodenal) ulcers that are caused by bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it.

What are the possible side effects of Rabeprazole Sodium Delayed-Release Tablets?

Rabeprazole Sodium Delayed-Release Tablets can cause serious side effects including:

• •
  See "What is the most important information I should know about Rabebprazole Sodium Delayed-Release Tablets?"
• •
  Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.
  
  
  
  Tell your doctor right away if you have any of these symptoms:
  • o
    seizures
  • o
    dizziness
  • o
    abnormal or fast heart beat
  • o
    jitteriness
  • o
    jerking movements or shaking (tremors)
  • o
    muscle weakness
  • o
    spasms of the hands and feet
  • o
    cramps or muscle aches
  • o
    spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking Rabeprazole Sodium Delayed-Release Tablets, during treatment, or if you will be taking Rabeprazole Sodium Delayed-Release Tablets for a long period of time.

The most common side effects with Rabeprazole Sodium Delayed-Release Tablets include:

• •
  headache
• •
  pain
• •
  sore throat
• •
  gas
• •
  infection
• •
  constipation

Other side effects:

• •
  Serious allergic reactions. Tell your doctor if you have any of the following symptoms with Rabeprazole Sodium Delayed-Release Tablets.
• •
  rash
• •
  face swelling
• •
  throat tightness
• •
  difficulty breathing

Your doctor may stop Rabeprazole Sodium Delayed-Release Tablets if these symptoms happen.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of Rabeprazole Sodium Delayed-Release Tablets. For more information, ask your doctor or pharmacist.

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

How should I store Rabeprazole Sodium Delayed-Release Tablets?

• •
  Store Rabeprazole Sodium Delayed-Release Tablets in a dry place at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Rabeprazole Sodium Delayed-Release Tablets and all medicines out of the reach of children.

General Information about Rabeprazole Sodium Delayed-Release Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Rabeprazole Sodium Delayed-Release Tablets for a condition for which it was not prescribed. Do not give Rabeprazole Sodium Delayed-Release Tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Rabeprazole Sodium Delayed-Release Tablets. If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Rabeprazole Sodium Delayed-Release Tablets that is written for healthcare professionals. For more information, go to http://www.kremersurban.com/ or call 1-866-822-0068.

What are the ingredients in Rabeprazole Sodium Delayed-Release Tablets?

Active Ingredient: rabeprazole sodium

Inactive Ingredients: crospovidone, FD&C Blue #1, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, talc and triethyl citrate.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Distributed by:

Kremers Urban Pharmaceuticals Inc.

Princeton, NJ 08540, USA

Repackaged and Relabeled by:

Proficient Rx LP

Thousand Oaks, CA 91320

CIA76375B

Rev. 2E 10/2013

All brand names are the trademarks of their respective owners.

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

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.

There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2) ].

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.

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January 2000.

The active ingredient in Rabeprazole Sodium Delayed-Release Tablets 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 formula is:

Rabeprazole Sodium Delayed-Release Tablets 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 crospovidone, FD&C Blue #1, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, talc and triethyl citrate.

Concomitant administration of rabeprazole and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel [see Clinical Pharmacology (12.3) ]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Rabeprazole Sodium Delayed-Release Tablets.

In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC₅₀ of 62 micromolar, a concentration that is over 50 times higher than the C_max in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.6) ].

Several published observational studies in adults suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.2) ].

Of the total number of subjects in clinical studies of Rabeprazole Sodium Delayed-Release Tablets, 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.

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2) ].

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

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with Rabeprazole Sodium Delayed-Release Tablets, refer to the Contraindications section of their package inserts.

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.

• •
  Increased INR and prothrombin times have been reported with concomitant use with warfarin. Patients need to be monitored (7.2)
• •
  Rabeprazole has been shown to inhibit cyclosporine metabolism in vitro (7.3)
• •
  Rabeprazole Sodium Delayed-Release Tablets inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, iron salts and digoxin) (7.4)
• •
  Rabeprazole Sodium Delayed-Release Tablets may reduce the plasma levels of atazanavir (7.4)
• •
  Methotrexate: Rabeprazole Sodium Delayed-Release Tablets may increase serum level of methotrexate (7.7)

It is not known if Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets is administered to a nursing woman.

Rabeprazole Sodium 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 Rabeprazole Sodium Delayed-Release Tablets, peak plasma concentrations (C_max) of rabeprazole occur over a range of 2 to 5 hours (T_max). The rabeprazole C_max 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.

Rabeprazole Sodium Delayed-Release Tablets is a proton pump inhibitor (PPI) indicated in adults for:

• •
  Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)(1.1)
• •
  Maintenance of Healing of Erosive or Ulcerative GERD (1.2)
• •
  Treatment of Symptomatic GERD (1.3)
• •
  Healing of Duodenal Ulcers (1.4)
• •
  Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (1.5)
• •
  Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (1.6)

In adolescent patients 12 years of age and older for:

• •
  Short-term treatment of Symptomatic GERD (1.7)

Rabeprazole Sodium Delayed-Release Tablets in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.5) and Dosage and Administration (2.5) ].

In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see Clinical Pharmacology (12.2) and the clarithromycin package insert, Clinical Pharmacology (12.2) ].

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.

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.

Published observational studies suggest that PPI therapy like Rabeprazole Sodium Delayed-Release Tablets may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with Rabeprazole Sodium Delayed-Release Tablets, refer to Warnings and Precautions sections of those package inserts.

• •
  Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy (5.1)
• •
  Use with warfarin: monitor for increases in INR and prothrombin time (5.2)
• •
  PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea (5.3)
• •
  Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (5.4)
• •
  Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.5)

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

Rabeprazole Sodium Delayed-Release Tablets are provided in strength of 20 mg.

The following adverse reactions have been identified during post approval use of Rabeprazole Sodium Delayed-Release Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sudden death; coma, hyperammonemia; jaundice; rhabdomyolysis; disorientation and delirium; anaphylaxis; angioedema; bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; interstitial pneumonia; interstitial nephritis; TSH elevations, bone fractures, hypomagnesemia and Clostridium difficile associated diarrhea. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported. Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.

• •
  The safety and efficacy of Rabeprazole Sodium Delayed-Release Tablets for GERD have not been established for pediatric patients less than 12 years of age (8.4).
• •
  The safety and efficacy of Rabeprazole Sodium Delayed-Release Tablets for the other adult indications have not been established for pediatric patients (8.4).

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.

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.

See FDA-approved patient labeling (Error! Hyperlink reference not valid.).

How to Take Rabeprazole Sodium Delayed-Release Tablets

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

Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.3) ].

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.

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.

Rabeprazole Sodium Delayed-Release Tablets 20 mg is supplied as delayed-release blue enteric-coated round tablets debossed with "KU" on one side and "7" on the other.

Rabeprazole Sodium Delayed-Release Tablets 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.

The recommended adult oral dose is one Rabeprazole Sodium 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 (1.4) ]. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.

In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Rabeprazole Sodium Delayed-Release Tablets QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole Sodium Delayed-Release Tablets 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 Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets and omeprazole were comparable in providing complete resolution of symptoms.

Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 postpartum and followed by a 13-week recovery period. Rats were dosed at 5, 25 or 150 mg/kg/day and dogs were dosed at 3, 10 or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs.

Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults.

The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for 4 weeks [see Indications and Usage (1.3) ]. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. The recommended adolescent dosing is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for 8 weeks.

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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

Rabeprazole Sodium

Delayed-Release

Tablets

20 mg

Rx Only

PHARMACIST: Dispense the

accompanying Medication Guide

to each patient.

Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.3) ].

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin] [see Drug Interactions in prescribing information for amoxicillin].

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.

Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets may be considered.

The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for four to eight weeks [see Indications and Usage (1.1) ]. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole Sodium Delayed-Release Tablets may be considered.

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 Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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):

Rabeprazole Sodium Delayed-Release Tablets 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 Sodium Delayed-Release Tablets 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.

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_max 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.

In a 88/104-week carcinogenicity study in CD-1 mice, rabeprazole at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to rabeprazole (AUC) of 1.40 µg∙hr/mL which is 1.6 times the human exposure (plasma AUC_0-∞ = 0.88 µg∙hr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week carcinogenicity study in p53^+/- transgenic mice, rabeprazole at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to rabeprazole at 200 mg/kg/day is about 17-24 times the human exposure at the recommended dose for GERD. In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30 and 60 mg/kg/day and females with 5, 15, 30, 60 and 120 mg/kg/day. Rabeprazole produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to rabeprazole (AUC) of about 0.1 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.

Rabeprazole Sodium Delayed-Release Tablets 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.

The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily [see Indications and Usage (1.2) ].

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 Sodium Delayed-Release Tablets QD or placebo. As demonstrated in the tables below, Rabeprazole Sodium Delayed-Release Tablets 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:

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7.7) ].

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

Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.

The recommended oral dose for adolescents 12 years of age and older is one 20 mg Delayed-Release Tablet once daily for up to 8 weeks [see Use in Specific Populations (8.4) and Clinical Studies (14.7) ].

Rabeprazole Sodium Delayed-Release Tablets is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

The dosage of Rabeprazole Sodium Delayed-Release Tablets in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. 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 Sodium Delayed-Release Tablets for up to one year.