RABEPRAZOLE SODIUM- rabeprazole sodium_tablet, delayed release

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 + + In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro The antisecretory effect begins within one hour after oral administration of 20 mg rabeprazole sodium delayed-release tablets. The median inhibitory effect of rabeprazole sodium on 24 hour gastric acidity is 88 % of maximal after the first dose. A 20 mg dose of rabeprazole sodium 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) + + 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. 8 Stimulated Acid Output (mmol/hr) 0. 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 *(p<0. 001 versus placebo) Rabeprazole Sodium Delayed-Release Tablets AUC interval (hrs) 10 mg (N=24) 20 mg (N=24) 40 mg (N=24) Placebo (N=24) 08:00 en dash 13:00 19. 7 13:00 en dash 19:00 5. 7 19:00 en dash 22:00 0. 5 22:00 en dash 08:00 129. 2+/-84 * 109. 9+/-165 AUC 0-24 hours 155. 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) Table 5: Gastric Acid Parameters Rabeprazole Sodium Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8 a b * Rabeprazole sodium delayed-release tablets 20 mg once daily Placebo Parameter Day 1 Day 8 Day 1 Day 8 Mean AUC 0-24 340. 4 Median trough pH (23-hr) a 3. 38 % Time Gastric pH greater than 3 b 54. 7 % Time Gastric pH greater than 4 b 44. 0 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. 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 20 mg and in 100% of subjects receiving rabeprazole sodium 40 mg. With rabeprazole sodium 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. 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. 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. 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 beta-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 6beta-hydroxycortisol, serum testosterone and circadian cortisol profile. 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. After oral administration of 20 mg rabeprazole sodium delayed-release tablets, peak plasma concentrations (C max max max Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When rabeprazole sodium delayed-release tablets are administered with a high fat meal, T max max Rabeprazole is 96. 3% bound to human plasma proteins. Metabolism : Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro Excretion: Following a single 20 mg oral dose of 14 Age: Geriatric Population In 20 healthy elderly subjects administered 20 mg rabeprazole sodium delayed-release tablets once daily for seven days, AUC values approximately doubled and the C max [see USE IN SPECIFIC POPULATION ( 8. 5 Age: Pediatric Population The pharmacokinetics of rabeprazole was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received 20 mg rabeprazole sodium delayed-release tablets once daily for five or seven days. An approximate 40% increase in rabeprazole exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult subjects. Sex and Race/Ethnicity: In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC 0-infinity Renal Impairment: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance <=5 mL/min/1. 73 m 2 Hepatic Impairment: In a single dose study of 10 patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a single 20 mg dose of rabeprazole sodium delayed-release tablets, AUC 0-24 In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, AUC 0-infinity max No information exists on rabeprazole disposition in patients with severe hepatic impairment (Child-Pugh Class C) [see USE IN SPECIFIC POPULATIONS ( 8. 6 Combined Administration with Antimicrobials: Sixteen healthy subjects genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg rabeprazole sodium delayed-release tablets, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and C max max max Antacids: Co-administration of rabeprazole sodium delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as theophylline (CYP1A2) given as single oral doses, diazepam (CYP2C9 and CYP3A4) as a single intravenous dose, and phenytoin (CYP2C9 and CYP2C19) 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. Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with 20 mg rabeprazole sodium delayed-release tablets (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81. 5%) when rabeprazole sodium delayed-release tablets were coadministered compared to administration of clopidogrel with placebo [see DRUG INTERACTIONS ( 7 Digoxin: In healthy adult subjects (n=16), co-administration of 20 mg rabeprazole sodium delayed-release tablets with 2. 5 mg once daily doses of digoxin at steady state resulted in approximately 29% and 19% increase in mean C max (0-24) [see DRUG INTERACTIONS ( 7 Ketoconazole: In healthy adult subjects (n=19), co-administration of 20 mg rabeprazole sodium delayed-release tablets at steady state with a single 400 mg oral dose ketoconazole resulted in approximately an average of 31% reduction in both C max (0-inf) [see DRUG INTERACTIONS ( 7 Cyclosporine: In vitro 50 max The following in vitro Rabeprazole sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro [see INDICATIONS AND USAGE ( 1 CLINICAL STUDIES ( 14. 5 Susceptibility testing of H. pylori 1 Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC >=1 mcg/mL) to H. pylori For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin. Table 6: Clarithromycin Susceptibility Test Results and Clinical/ Bacteriologic Outcomes a a b Days of RAC Therapy Clarithromycin Pretreatment Results Total Number H. pylori (Eradicated) H. pylori Post-Treatment Susceptibility Results S b I b R b No MIC 7 Susceptible b 129 103 2 0 1 23 7 Intermediate b 0 0 0 0 0 0 7 Resistant b 16 5 2 1 4 4 10 Susceptible b 133 111 3 1 2 16 10 Intermediate b 0 0 0 0 0 0 10 Resistant b 9 1 0 0 5 3 Patients with persistent H. pylori In the U. multicenter study, greater than 99% (558/560) of patients had H. pylori In a clinical study in evaluating rabeprazole sodium delayed-release tablets in Japanese 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. The clinical relevance of this is not known. 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.

Rabeprazole sodium delayed-release tablet is a proton-pump inhibitor (PPI) indicated in adults for: 1. 4 Helicobacter pylori 1. 6 In adolescent patients 12 years of age and older for: 1. 7 Rabeprazole sodium delayed-release tablets are 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. Rabeprazole sodium delayed-release tablets are 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. Rabeprazole sodium delayed-release tablets are indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks. Rabeprazole sodium delayed-release tablets are indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks. Rabeprazole sodium delayed-release tablets, in combination with amoxicillin and clarithromycin as a three drug regimen, are indicated for the treatment of patients with H. pylori 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. Rabeprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. Rabeprazole sodium delayed-release tablets are indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.

Indication Recommended Dosage (2) Healing of Erosive or Ulcerative Gastroesophageal 20 mg once daily for 4 to 8 weeks Maintenance of Healing of Erosive or Ulcerative 20 mg once daily* Symptomatic GERD in Adults 20 mg once daily for 4 weeks Healing of Duodenal Ulcers 20 mg once daily after morning meal Helicobacter pylori Three Drug Regimen: Rabeprazole sodium delayed-release All three medications should be taken twice daily with morning and evening meals for 7 days. Pathological Hypersecretory Conditions, Including Starting dose 60 mg once daily then Symptomatic GERD in Adolescents 12 Years of Age 20 mg once daily for up to 8 weeks Administration Instructions ( 2 ) Swallow rabeprazole sodium delayed-release tablets whole. Do not chew, crush or split the tablets. Helicobacter pylori Table 1 shows the recommended dosage of rabeprazole delayed-release tablets in adults and adolescent patients 12 years of age and older. The use of rabeprazole delayed-release tablets is not recommended for use in pediatric patients 1 year to less than 12 years of age because the lowest available tablet strength (20 mg) exceeds the recommended dose for these patients. Use another rabeprazole formulation for pediatric patients 1 year to less than 12 years of age. Table 1: Recommended Dosage and Duration of Rabeprazole Delayed-Release Tablets in Adults and Adolescents 12 Years of Age and Older * For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of rabeprazole may be considered. ** If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. *** Most patients heal within 4 weeks; some patients may require additional therapy to achieve healing. Indication Dosage of Rabeprazole delayed-release tablets Treatment Duration Adults Healing of Erosive or Ulcerative Gastroesophageal 20 mg once daily 4 to 8 weeks* Maintenance of Healing of Erosive or Ulcerative GERD 20 mg once daily Controlled studies do not extend Symptomatic GERD in Adults 20 mg once daily Up to 4 weeks** Healing of Duodenal Ulcers 20 mg once daily after the morning meal Up to 4 weeks*** Helicobacter pylori Rabeprazole 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg Take all three medications twice daily with morning and evening meals; it is important that patients comply with the full 7-day regimen [see CLINICAL STUDIES ( 14. 5 7 days Pathological Hypersecretory Conditions, Including Starting dose 60 mg once daily then adjust to patient needs; As long as clinically indicated Adolescents 12 Years of Age and Older Symptomatic GERD 20 mg once daily Up to 8 weeks Administration Instructions Helicobacter pylori .

1 To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www. gov/medwatch. The following serious adverse reactions are described below and elsewhere in labeling: [see WARNINGS AND PRECAUTIONS ( 5. 3 Clostridium difficile- [see WARNINGS AND PRECAUTIONS ( 5. 4 [see WARNINGS AND PRECAUTIONS ( 5. 5 [see WARNINGS AND PRECAUTIONS ( 5. 6 [see WARNINGS AND PRECAUTIONS ( 5. 7 [see WARNINGS AND PRECAUTIONS ( 5. 8 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 to 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. 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. 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 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. The related reported adverse reactions that occurred in >=2% of patients were headache (5. 4%) and nausea (1. There were no adverse reactions reported in this study that were not previously observed in adults. The following adverse reactions have been identified during post approval use of rabeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sudden death; coma; hyperammonemia; jaundice; rhabdomyolysis; disorientation and delirium; anaphylaxis; angioedema; systemic lupus erythematosus, bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus, and erythema multiforme; interstitial pneumonia; interstitial nephritis; TSH elevations; bone fractures; hypomagnesemia and Clostridium difficile-.

4 4 7 4 [see ADVERSE REACTIONS ( 6 PPIs, including rabeprazole sodium delayed-release tablets, are contraindicated with rilpivirine-containing products [see DRUG INTERACTIONS ( 7 )]. CONTRAINDICATIONS.

Pediatric Use 2 8. 4 Risk Summary There are no available human data on rabeprazole sodium delayed-release tablets use in pregnant women to inform the drug associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No evidence of adverse developmental effects were seen in animal reproduction studies with rabeprazole administered during organogenesis at 13 and 8 times the human area under the plasma concentration-time curve (AUC) at the recommended dose for GERD, in rats and rabbits, respectively [see Data]. Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation [ Data] Data Animal Data: Embryo-fetal developmental studies have been performed in rats during organogenesis at intravenous doses of rabeprazole up to 50 mg/kg/day (plasma AUC of 11. 8 mcghr/mL, about 13 times the human exposure at the recommended oral dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7. 3 mcghr/mL, about 8 times the human exposure at the recommended oral dose for GERD) and have revealed no evidence of harm to the fetus due to rabeprazole. Administration of rabeprazole to rats in late gestation and during lactation at an oral dose of 400 mg/kg/day (about 195-times the human oral dose based on mg/m 2 A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with a different PPI at about 3. 4 to 57 times an oral human dose on a body surface area basis. Decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate, and minimal to mild bone marrow hypocellularity were noted at doses of this PPI equal to or greater than 3. 4 times an oral human dose on a body surface area basis. Physeal dysplasia in the femur was also observed in offspring after in utero and lactational exposure to the PPI at doses equal to or greater than 33. 6 times an oral human dose on a body surface area basis. Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when the PPI was administered at oral doses of 3. When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 33. Risk Summary Lactation studies have not been conducted to assess the presence of rabeprazole in human milk, the effects of rabeprazole on the breastfed infant, or the effects of rabeprazole on milk production. Rabeprazole is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for rabeprazole sodium and any potential adverse effects on the breastfed infant from rabeprazole sodium or from the underlying maternal condition. The safety and effectiveness of rabeprazole sodium delayed-release tablets have been established in pediatric patients for adolescent patients 12 years of age and older for the treatment of symptomatic GERD. Use of rabeprazole sodium delayed-release tablets in this age group is supported by adequate and well controlled studies in adults and a multicenter, randomized, open-label, parallel-group study in 111 adolescent patients 12 to 16 years of age. Patients had a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD and were randomized to either 10 mg or 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse reaction profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in >=2% of patients were headache (5%) and nausea (2%). There were no adverse reactions reported in these studies that were not previously observed in adults. The safety and effectiveness of rabeprazole sodium delayed-release tablets have not been established in pediatric patients for: Healing of Erosive or Ulcerative GERD Helicobacter pylori Rabeprazole sodium delayed-release 20 mg tablets are not recommended for use in pediatric patients less than 12 years of age because the tablet strength exceeds the recommended dose for these patients [see DOSAGE AND ADMINISTRATION ( 2 Juvenile Animal Data Studies in juvenile and young adult rats and dogs were performed. In juvenile animal studies rabeprazole sodium was administered orally to rats for up to 5 weeks and to dogs for up to 13 weeks, each commencing on Day 7 post-partum and followed by a 13-week recovery period. Rats were dosed at 5, 25, or 150 mg/kg/day and dogs were dosed at 3, 10, or 30 mg/kg/day. The data from these studies were comparable to those reported for young adult animals. Pharmacologically mediated changes, including increased serum gastrin levels and stomach changes, were observed at all dose levels in both rats and dogs. These observations were reversible over the 13-week recovery periods. Although body weights and/or crown-rump lengths were minimally decreased during dosing, no effects on the development parameters were noted in either juvenile rats or dogs. When juvenile animals were treated for 28 days with a different PPI at doses equal to or greater than 34 times the daily oral human dose on a body surface area basis, overall growth was affected and treatment-related decreases in body weight (approximately 14%) and body weight gain, and decreases in femur weight and femur length were observed. Of the total number of subjects (n=2009) 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. Administration of rabeprazole sodium delayed-release tablets to patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) resulted in increased exposure and decreased elimination [see CLINICAL PHARMACOLOGY ( 12. 3 [see WARNINGS AND PRECAUTIONS ( 5 6.

RECENT MAJOR CHANGES
Contraindications ( 4 Warnings and Precautions, Cutaneous and Systemic Lupus Erythematosus ( 5.6
DRUG INTERACTIONS
See full prescribing information for a list of clinically important drug interactions ( 7 Table 2 includes drugs with clinically important drug interactions 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 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. Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS ( 4 Atazanavir: Intervention: Nelfinavir: Saquinavir: Other antiretrovirals: 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. , iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole) Clinical Impact: Rabeprazole can reduce the absorption of 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, 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. Intervention: See CONTRAINDICATIONS WARNINGS AND PRECAUTIONS DRUG INTERACTIONS.

OVERDOSAGE
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 once daily. 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. If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
NONCLINICAL TOXICOLOGY
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 mcghr/mL which is 1.6 times the human exposure (plasma AUC 0-infinity +/- 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+/en dash) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Rabeprazole was negative in the in vitro in vivo in vivo ex vivo Rabeprazole at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 mcghr/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.
CLINICAL STUDIES
, 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 once daily. 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: Table 7: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed *(p<0. 001 versus placebo) Rabeprazole sodium delayed-release tablets Week 10 mg once daily N=27 20 mg once daily N=25 40 mg once daily N=26 Placebo N=25 4 63 %* 56 %* 54 %* 0 % 8 93 %* 84 %* 85 %* 12 % In addition, there was a statistically significant difference in favor of the rabeprazole sodium 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. All rabeprazole sodium groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p<=0. Mean reductions from baseline in daily antacid dose were statistically significant for all rabeprazole sodium groups when compared to placebo at both Weeks 4 and 8 (p<=0. In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, the percentage of patients healed at endoscopy after four and eight weeks of treatment was statisticially superior in the patients treated with rabeprazole sodium delayed-release tablets compared to ranitidine: Table 8: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed *(p<0. 001 versus ranitidine) Week 20 mg Rabeprazole sodium delayed-release tablets once daily N=167 Ranitidine 150 mg four times daily N=169 4 59 %* 36 % 8 87 %* 66 % A dose of 20 mg once daily of rabeprazole sodium delayed-release tablets was significantly more effective than ranitidine 150 mg four times daily in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0. Rabeprazole sodium 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. The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg once daily for 4 to 8 weeks. The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U. 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 once daily or placebo. As demonstrated in Tables 10 and 11 below, patients treated with rabeprazole sodium delayed-release tablets were 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. The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg once daily. Table 9: Percent of Patients in Endoscopic Remission *(p<0. 001 versus placebo) Rabeprazole sodium delayed-release tablets 10 mg once daily 20 mg once daily Placebo Study 1 N=66 N=67 N=70 Week 4 83 %* 96 %* 44 % Week 13 79 %* 93 %* 39 % Week 26 77 %* 93 %* 31 % Week 39 76 %* 91 %* 30 % Week 52 73 %* 90 %* 29 % Study 2 N=93 N=93 N=99 Week 4 89 %* 94 %* 40 % Week 13 86 %* 91 %* 33 % Week 26 85 %* 89 %* 30 % Week 39 84 %* 88 %* 29 % Week 52 77 %* 86 %* 29 % COMBINED STUDIES N=159 N=160 N=169 Week 4 87 %* 94 %* 42 % Week 13 83 %* 92 %* 36 % Week 26 82 %* 91 %* 31 % Week 39 81 %* 89 %* 30 % Week 52 75 %* 87 %* 29 % Table 10: Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime Heartburn Severity at Week 52 * p<=0. 001 versus placebo dagger Rabeprazole sodium delayed-release tablets Placebo 10 mg once daily 20 mg once daily Heartburn Frequency Study 1 46/55 (84 %)* 48/52 (92 %)* 17/45 (38 %) Study 2 50/72 (69 %)* 57/72 (79 %)* 22/79 (28 %) Daytime Heartburn Severity Study 1 61/64 (95 %)* 60/62 (97 %)* 42/61 (69 %) Study 2 73/84 (87 %) dagger 82/87 (94 %)* 67/90 (74 %) Nighttime Heartburn Severity Study 1 57/6 (93 %)* 60/61 (98 %)* 37/56 (66 %) Study 2 67/80 (84 %) 79/87 (91 %) dagger 64/87 (74 %) Two U. , 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 20 mg rabeprazole sodium delayed-release tablets compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for rabeprazole sodium 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 20 mg of rabeprazole sodium delayed-release tablets significantly improved other GERD-associated symptoms (regurgitation, belching, and early satiety) by week 4 compared with placebo (all p values < 0. A dose of 20 mg rabeprazole sodium delayed-release tablets also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0. The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg once daily for 4 weeks. image-02 image03 Image-04 Image05 In a U. , randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of rabeprazole sodium delayed-release tablets once daily versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole sodium was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below: Table 11: Healing of Duodenal Ulcers Percentage of Patients Healed * p<=0. 001 versus placebo Rabeprazole sodium delayed-release tablets Week 20 mg once daily N=34 40 mg once daily N=33 Placebo N=33 2 44 % 42 % 21 % 4 79 %* 91 %* 39 % At Weeks 2 and 4, significantly more patients in the rabeprazole sodium 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 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0. Significant differences in resolution of daytime and nighttime pain were noted in both rabeprazole sodium 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 groups compared to placebo at Weeks 2 and 4 (p<0. An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg rabeprazole sodium delayed-release tablets once daily with 20 mg omeprazole once daily. The study was designed to provide at least 80% power to exclude a difference of at least 10% between rabeprazole sodium 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 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: Table 12: Healing of Duodenal Ulcers Percentage of Patients Healed Week Rabeprazole sodium delayed-release tablets 20 mg once daily N=102 Omeprazole 20 mg once daily N=103 95% Confidence Interval for the Treatment Difference (Rabeprazole Sodium - Omeprazole) 2 69 % 61 % (en dash6%, 22%) 4 98 % 93 % (en dash3%, 15%) Rabeprazole sodium and omeprazole were comparable in providing complete resolution of symptoms. multicenter study was a double-blind, parallel-group comparison of rabeprazole sodium delayed-release tablets, 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 13 H. pylori Table 13: Helicobacter pylori Eradication at >= 6 Weeks After the End of Treatment a H. pylori 13 b H. pylori * The 95% confidence intervals for the difference in eradication rates for 7-day RAC minus 10-day RAC are (-9. 0) in the PP population and (-9. 5) in the ITT population. Treatment Group Percent (%) of Patients Cured (Number of Patients) Difference (RAC en dash OAC) [95% Confidence Interval] 7-day RAC* 10-day OAC Per Protocol a 84. 8 Intent-to-Treat b 77. 0 10-day RAC* 10-day OAC Per Protocol a 86. 4 Intent-to-Treat b 78. 8 3-day RAC 10-day OAC Per Protocol a 29. 6 Intent-to-Treat b 27. 0 The recommended dosage of rabeprazole sodium delayed-release tablets is 20 mg twice daily with amoxicillin and clarithromycin for 7 days. 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 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 also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of rabeprazole sodium used to treat this small cohort of patients with gastric hypersecretion were well tolerated. The recommended starting dosage of rabeprazole sodium delayed-release tablets is 60 mg once daily.
REFERENCES
1. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard

Proficient Rx LP

RABEPRAZOLE SODIUM- rabeprazole sodium_tablet, delayed release Product manual source documgent