Rabeprazole

INDICATIONS AND USAGE 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 ) 1.1 Healing of Erosive or Ulcerative GERD in Adults 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. 1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults 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. 1.3 Treatment of Symptomatic GERD in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults. 1.4 Healing of Duodenal Ulcers in Adults 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. 1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults 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) ]. 1.6 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome. 1.7 Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older 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.

DOSAGE AND ADMINISTRATION Rabeprazole Sodium Delayed-Release Tablets should be swallowed whole. The tablets should not be chewed, crushed, or split ( 2.10 ). Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) ( 2.1 ) 20 mg once daily Maintenance of Healing of Erosive or Ulcerative GERD ( 2.2 ) 20 mg once daily Treatment of Symptomatic GERD in Adults ( 2.3 ) 20 mg once daily Healing of Duodenal Ulcers ( 2.4 ) 20 mg once daily after morning meal Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence ( 2.5 ) Three Drug Regimen: Rabeprazole Sodium Delayed-Release Tablets 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg All three medications should be taken twice daily with morning and evening meals for 7 days Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ( 2.6 ) Starting dose 60 mg once daily then adjust to patient needs Treatment of Symptomatic GERD in Adolescents 12 Years of Age and Older ( 2.7 ) 20 mg once daily 2.1 Healing of Erosive or Ulcerative GERD in Adults 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. 2.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults 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) ]. 2.3 Treatment of Symptomatic 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. 2.4 Healing of Duodenal Ulcers in Adults 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. 2.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults TABLE 1 THREE DRUG REGIMEN It is important that patients comply with the full 7-day regimen [ see Clinical Studies (14.5) ]. All three medications should be taken twice daily with the morning and evening meals. Rabeprazole Sodium Delayed-Release Tablet 20 mg Twice Daily for 7 Days Amoxicillin 1000 mg Twice Daily for 7 Days Clarithromycin 500 mg Twice Daily for 7 Days 2.6 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults 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. 2.7 Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older The recommended oral dose for adolescents 12 years of age and older is one 20 mg Delayed-Release Tablet once daily for up to 8 weeks [ see Use in Specific Populations (8.4) and Clinical Studies (14.7) ]. 2.9 Elderly, Renal and Hepatic Impaired Patients No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients. 2.10 Administration Recommendations TABLE 2 Administration Recommendations Formulation Population Instructions Delayed-Release Tablet Adults and adolescents 12 years of age and older Swallow tablets whole. Do not chew, crush or split tablets. Tablets can be taken with or without food.

WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing ( 5.1 ). Use with Warfarin : Monitor for increases in INR and prothrombin time ( 5.2 , 7 ). Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients ( 5.3 ). Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk of ( 5.4 ). 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 ( 5.5 ). Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutatneous adverse reactions or other signs of hypersensitivity and consider further evaluation ( 5.6 ). Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous, new onset or exacerbation of existing disease; discontinue rabeprazole sodium delayed-release tablets and refer to specialist for evaluation ( 5.7 ). Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin ( 5.8 ). Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs ( 5.9 ). Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of rabeprazole sodium delayed-release tablets ( 5.10 , 7 ). Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy ( 5.11 ). 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with rabeprazole sodium delayed-release tablets does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. 5.2 Interaction with Warfarin Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with rabeprazole sodium delayed-release tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time [see Drug Interactions ( 7 )] . 5.3 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue rabeprazole sodium and evaluate patients with suspected acute TIN [see Contraindication ( 4 )]. 5.4 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like rabeprazole sodium 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, refer to Warnings and Precautions sections of the corresponding prescribing information. 5.5 Bone Fracture Several published observational studies in adults suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration ( 2 ), Adverse Reactions ( 6.2 ) ] . 5.6 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions ( 6.2 )] . Discontinue rabeprazole sodium delayed-release tablets at first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. 5.7 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including rabeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving rabeprazole sodium, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.8 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with rabeprazole sodium delayed-release tablets. 5.9 Hypomagnesemia and Mineral Metabolism 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. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. 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 c

CONTRAINDICATIONS • Patients with a history of hypersensitivity to rabeprazole ( 4 ). • PPIs, including rabeprazole sodium delayed-release tablets, are contraindicated in patients receiving rilpivirine-containing products ( 4 , 7 ). • Refer to the Contraindications section of the prescribing information for clarithromycin and amoxicillin, when administered in combination with rabeprazole sodium delayed-release tablets ( 4 ). • Rabeprazole sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6 )] . • PPIs, including rabeprazole sodium delayed-release tablets, are contraindicated with rilpivirine-containing products [see Drug Interactions ( 7 )]. • 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.

DRUG INTERACTIONS Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with rabeprazole sodium delayed-release tablets and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole sodium delayed-release tablets and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity . • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. Intervention: Rilpivirine-containing products : Concomitant use with rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications ( 4) ] . See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, 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 )] . Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Methotrexate Clinical Impact: Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.9 )]. Intervention: A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. Digoxin Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3 )]. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole) Clinical Impact: Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving rabeprazole sodium delayed-release tablets and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors . Intervention: Temporarily stop rabeprazole sodium delayed-release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma . Intervention: Temporarily stop treatment with rabeprazole sodium delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline. False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. See full prescribing information for a list of clinically important drug interactions ( 7 ).

ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.3) ] Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.4) ] Bone Fracture [see Warnings and Precautions (5.5) ] Sever Cutaneous Adverse Reactions [see Warnings and Precautions (5.6) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.7) ] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.8) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.9) ] Fundic Gland Polyps [see Warnings and Precautions (5.11) ] Most common adverse reactions in adults (>2%) are pain, pharyngitis, flatulence, infection, and constipation ( 6.1 ). Most common adverse reactions in adolescents (≥2%) are headache, diarrhea, nausea, vomiting, and abdominal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 866-488-0312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience 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. 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 per day of Rabeprazole Sodium delayed-release tablets. An analysis of adverse reactions appearing in ≥2% of patients treated with Rabeprazole Sodium delayed-release tablets (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 Sodium delayed-release tablets for 6 months and 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. Less common adverse reactions seen in controlled clinical trials (<2% of patients treated with Rabeprazole Sodium delayed-release tablets 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. Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively. No clinically significant laboratory abnormalities particular to the drug combinations were observed. For more information on adverse reactions or laboratory changes with amoxicillin or clarithromycin, refer to their respective prescribing information, Adverse Reactions section. Pediatrics In a multicenter, open-label study of adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to Rabeprazole Sodium delayed-release tablets that occurred in ≥2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in this study that were not previously observed in adults. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of rabeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and Lymphatic System Disorders: agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia Ear and Labyrinth Disorders: vertigo Eye Disorders: blurred vision Gastrointestinal Disorders: fundic gland polyps General Disorders and Administration Site Conditions: sudden death Hepatobiliary Disorders: jaundice Immune System Disorders: anaphylaxis, angioedema, systemic lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), DRESS, AGEP Infections and Infestations: Clostridium difficile -associated diarrhea Investigations: Increases in prothrombin time/INR (in patients treated with concomitant warfarin), TSH elevations Metabolism and Nutrition Disorders: hyperammonemia, hypomagnesemia, hypocalcemia, hypokalemia [ Warnings and Precautions 5.8 ] , hyponatremia Musculoskeletal System Disorders: bone fracture, rhabdomyolysis Nervous System Disorders: coma Psychiatric Disorders: delirium, disorientation Renal and Urinary Disorders: interstitial nephritis Respiratory, Thoracic and Mediastinal Disorders: interstitial pneumonia Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions including bullous and other drug eruptions of the skin, cutaneous lupus erythematosus, erythema multiforme

Mechanism of Action Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds. 12.2 Pharmacodynamics Antisecretory Activity The antisecretory effect begins within one hour after oral administration of 20 mg rabeprazole sodium delayed-release tablets. The median inhibitory effect of rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose. A 20 mg dose of rabeprazole sodium delayed-release tablets inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1 to 2 hours) reflects the sustained inactivation of the H+, K+ATPase. Table 3: Gastric Acid Parameters: Rabeprazole Sodium Delayed-Release Tablets versus Placebo After 7 Days of Once Daily Dosing *(p<0.01 versus placebo) Parameter Rabeprazole sodium delayed-release tablets (20 mg once daily) Placebo Basal Acid Output (mmol/hr) 0.4* 2.8 Stimulated Acid Output (mmol/hr) 0.6* 13.3 % Time Gastric pH>3 65* 10 Compared to placebo, 10 mg, 20 mg, and 40 mg of rabeprazole sodium delayed-release tablets, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below. Table 4: AUC Acidity (Mmol•Hr/L): Rabeprazole Sodium Delayed-Release Tablets versus Placebo on Day 7 of Once Daily Dosing (Mean±SD) *(p<0.001 versus placebo) AUC interval (hrs) Rabeprazole sodium delayed-release tablets Placebo (N=24) 10 mg (N=24) 20 mg (N=24) 40 mg (N=24) 08:00 – 13:00 19.6±21.5* 12.9±23* 7.6±14.7* 91.1±39.7 13:00 – 19:00 5.6±9.7* 8.3±29.8* 1.3±5.2* 95.5±48.7 19:00 – 22:00 0.1±0.1* 0.1±0.06* 0.0±0.02* 11.9±12.5 22:00 – 08:00 129.2±84* 109.6±67.2* 76.9±58.4* 479.9±165 AUC 0-24 hours 155.5±90.6* 130.9±81* 85.8±64.3* 678.5±216 After administration of 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, the mean percent of time that gastric pH greater than 3 or gastric pH greater than 4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg rabeprazole sodium delayed-release tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below: Table 5: Gastric Acid Parameters Rabeprazole Sodium Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8 a No inferential statistics conducted for this parameter. b Gastric pH was measured every hour over a 24-hour period. * (p<0.001 versus placebo) Parameter Rabeprazole sodium delayed-release tablets 20 mg once daily Placebo Day 1 Day 8 Day 1 Day 8 Mean AUC0-24 Acidity 340.8* 176.9* 925.5 862.4 Median trough pH (23-hr)a 3.77 3.51 1.27 1.38 % Time Gastric pH greater than 3b 54.6* 68.7* 19.1 21.7 % Time Gastric pH greater than 4b 44.1* 60.3* 7.6 11.0 Effects on Esophageal Acid Exposure In patients with GERD and moderate to severe esophageal acid exposure, a dose of 20 mg and 40 mg per day of rabeprazole sodium delayed-release tablets decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that the esophageal pH was less than 4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH greater than 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving rabeprazole sodium delayed-release tablets 20 mg and in 100% of subjects receiving rabeprazole sodium delayed-release tablets 40 mg. With rabeprazole sodium delayed-release tablets 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment. Effects on Serum Gastrin The median fasting gastrin level increased in a dose-related manner in patients treated once daily with rabeprazole sodium delayed-release tablets for up to eight weeks for ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease. The group median values stayed within the normal range. In a group of subjects treated with 20 mg rabeprazole sodium delayed-release tablets for 4 weeks a doubling of mean serum gastrin concentrations was observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. Effects on Enterochromaffin-like (ECL) Cells Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females [see NONCLINICAL TOXICOLOGY (13.1)]. In over 400 patients treated with rabeprazole sodium delayed-release tablets (10 or 20 mg) once daily for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats. Endocrine Effects Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male subjects treated with rabeprazole sodium delayed-release tablets for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile. Other Effects In humans treated with rabeprazole sodium delayed-release tablets for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with rabeprazole sodium delayed-release tablets and ocular effects. 12.3 Pharmacokinetics After oral administration of 20 mg rabeprazole sodium delayed-release tablets, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2 to 5 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing. Absorption Absolute bioavailabilit