Prescription Drugs

CLINICAL PHARMACOLOGY 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. Pharmacokinetics Absorption After oral administration to healthy adults of 10 mg ACIPHEX Sprinkle (delayed-release capsules opened and granules sprinkled on one tablespoon [15 mL] of applesauce) under fasting condition, median time (Tmax) to peak plasma concentrations (Cmax) of rabeprazole was 2.5 hours and ranged 1.0 to 6.5 hours. The plasma half-life of rabeprazole ranges from 1 to 2 hours. In healthy adults, a concomitant high fat meal delayed the absorption of rabeprazole from ACIPHEX Sprinkle (granules sprinkled on one tablespoon (15 mL) of applesauce) resulting in the median Tmax of 4.5 hours and decreased the Cmax and AUClast on average by 55% and 33%, respectively [see DOSAGE AND ADMINISTRATION]. When 10 mg ACIPHEX Sprinkle (granules) administered under fasting conditions to healthy adults on one tablespoon (15 mL) of applesauce, one tablespoon (15 mL) of yogurt, or when mixed with a small amount (5 mL) of liquid infant formula; the type of soft food did not significantly affect Tmax, Cmax and AUC of rabeprazole. Distribution Rabeprazole is 96.3% bound to human plasma proteins. Elimination 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 studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug. Excretion Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces. Specific Populations Pediatric Patients In patients with GERD 1 to 11 years of age, following once daily administration of ACIPHEX Sprinkle at doses from 0.14 to 1 mg/kg, the median time to peak plasma concentration ranged from 2 to 4 hours and the half-life was about 2.5 hours. No appreciable accumulation was noted following 5 days of dosing compared to exposure after a single dose. Based on population pharmacokinetic analysis, over the body weight range from 7 to 77 kg, the apparent rabeprazole clearance increased from 8.0 to 13.5 L/hr, an increase of 69%. The mean estimated total exposure i.e., AUC after a 10 mg dose of ACIPHEX Sprinkle in patients with GERD 1 to 11 years of age is comparable to AUC after 10 mg rabeprazole sodium delayed-release tablet in adults. Male And Female Patients And Racial Or Ethnic Groups In analyses of adult data 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, AUC0-∞ values for healthy Japanese men were approximately 50 to 60% greater than values derived from pooled data from healthy men in the United States. Patients With Renal Impairment In 10 adult patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after administration of rabeprazole 20 mg delayed-release tablets when compared to 10 healthy adult subjects. Patients With Hepatic Impairment In a single dose study of 10 adult patients with chronic mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a 20 mg dose of rabeprazole sodium delayed-release tablets, AUC0-24 was approximately doubled, the elimination half-life was 2-to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy adult men. In a multiple dose study of 12 adult patients with mild to moderate hepatic impairment administered 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age-and gender-matched subjects. These increases were not statistically significant. No information exists on rabeprazole disposition in patients with severe hepatic impairment (Child-Pugh Class C) [see Use In Specific Populations]. Drug Interaction Studies Effects Of Other Drugs On Rabeprazole Antacids Co-administration of rabeprazole sodium delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations. Effects Of Rabeprazole On Other Drugs Studies in healthy adult 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 adult 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 81.7 to 95.5%) when rabeprazole sodium delayed- release tablets was co-administered compared to administration of clopidogrel with placebo [see DRUG INTERACTIONS]. 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 Cmax and AUC(0-24) of digoxin [see DRUG INTERACTIONS]. 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 Cmax and AUC(0-inf) of ketoconazole [see DRUG INTERACTIONS]. Cyclosporine In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of ACIPHEX delayed-release tablets. This degree of inhibition is similar to that by omeprazole at equivalent concentrations. Pharmacogenomics In a clinical study in Japan 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. The clinical relevance of this is not known. 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. Clinical Studies The use of ACIPHEX Sprinkle in pediatric patients 1 to 11 years of age is supported by a two-part, multicenter, randomized, double-blind, parallel 2 dose arms clinical trial which was conducted in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment. Part 1 of the trial was 12 weeks in duration. Patients were randomized to one of two rabeprazole dose levels based on body weight. Patients weighing 6 to 14.9 kg received either 5 or 10 mg ACIPHEX Sprinkle, and those with body weight ≥15 kg received 10 mg ACIPHEX Sprinkle. Part 2 was a 24-week double-blinded extension of Part 1 (on same dose assigned in Part 1). Endoscopic evaluations were performed at 12 weeks (Part 1) and 36 weeks (Part 2) to assess esophageal healing. No prespecified formal hypothesis testing was conducted. For Part 1, rates of endoscopic healing were calculated and are shown in Table 3. Table 3: Short-Term (12-Week) Healing Rates In 1 To 11 Year Old Children (Part 1) Endoscopic Classification of GERD At Baseline Healing Rate at 12 weeks Body Weight Less than 15 kg Body Weight 15 kg or Greater 5 mg dose 10 mg dose 10 mg dose Erosivea 88% (7/8) 83% (5/6) 71% (12/17) Non-erosiveb 78% (7/9) 100% (10/10) 81% (17/21) a Hetzel-Dent score ≥2 b Hetzel-Dent score = 1 Of the 87 patients with healing in Part 1, 64 patients were enrolled into Part 2. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. Of the 52 patients with available data, healing was observed in 47 (90%) patients at 36 weeks. The recommended dosage of ACIPHEX Sprinkle is 5 mg once daily for 12 weeks in patients less than 15 kg with the option to increase to 10 mg once daily if there is an inadequate response. In patients 15 kg or greater, the recommended dosage is 10 mg once daily for 12 weeks.

CLINICAL PHARMACOLOGY 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. Pharmacodynamics Antisecretory Activity The antisecretory effect begins within one hour after oral administration of 20 mg ACIPHEX 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 ACIPHEX 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: ACIPHEX Delayed-Release Tablets versus Placebo After 7 Days of Once Daily Dosing Parameter ACIPHEX 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 *(p<0.01 versus placebo) Compared to placebo, 10 mg, 20 mg, and 40 mg of ACIPHEX 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): ACIPHEX Delayed-Release Tablets versus Placebo on Day 7 of Once Daily Dosing (Mean±SD) AUC interval (hrs) ACIPHEX delayed-release tablets Placebo (N=24) 10 mg (N=24) 20 mg (N=24) 40 mg (N=24) Day 8 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 *(p<0.001 versus placebo) After administration of 20 mg ACIPHEX 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 ACIPHEX 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 ACIPHEX Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8 Parameter ACIPHEX 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 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) 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 ACIPHEX 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 ACIPHEX 20 mg and in 100% of subjects receiving ACIPHEX 40 mg. With ACIPHEX 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 ACIPHEX 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 ACIPHEX 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]. In over 400 patients treated with ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX delayed-release tablets and ocular effects. Pharmacokinetics After oral administration of 20 mg ACIPHEX 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 bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When ACIPHEX delayed-release tablets are administered with a high fat meal, Tmax is variable; which concomitant food intake may delay the absorption up to 4 hours or longer. However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus ACIPHEX delayed-release tablets may be taken without regard to timing of meals. Distribution Rabeprazole is 96.3% bound to human plasma proteins. Elimination 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 studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug. Excretion Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces. Specific Populations Age Geriatric Population: In 20 healthy elderly subjects administered 20 mg ACIPHEX delayed-release tablets once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration [see Use In Specific Populations]. 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 ACIPHEX 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, AUC0-∞ values for healthy Japanese men were approximately 50 to 60% greater than values derived from pooled data from healthy men in the United States. Renal Impairment In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg dose of ACIPHEX delayed-release tablets when compared to 10 healthy subjects. 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 ACIPHEX delayed-release tablets, AUC0-24 was approximately doubled, the elimination half-life was 2-to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men. In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg ACIPHEX delayed-release tablets once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age-and gender-matched subjects. These increases were not statistically significant. No information exists on rabeprazole disposition in patients with severe hepatic impairment (Child-Pugh Class C) [see Use In Specific Populations]. Drug Interaction Studies Combined Administration With Antimicrobials Sixteen healthy subjects genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg ACIPHEX 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 Cmax for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the rabeprazole AUC and Cmax increased by 11% and 34%, respectively, following combined administration. The AUC and Cmax for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns. Effects Of Other Drugs On Rabeprazole Antacids: Co-administration of ACIPHEX delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations. Effects Of Rabeprazole On Other Drugs 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 ACIPHEX 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 81.7 to 95.5%) when ACIPHEX delayed-release tablets were coadministered compared to administration of clopidogrel with placebo [see DRUG INTERACTIONS]. 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 Cmax and AUC(0-24) of digoxin [see DRUG INTERACTIONS]. 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 Cmax and AUC(0-inf) of ketoconazole [see DRUG INTERACTIONS]. Cyclosporine: In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of ACIPHEX delayed-release tablets. This degree of inhibition is similar to that by omeprazole at equivalent concentrations. Microbiology The following in vitro data are available but the clinical significance is unknown. Rabeprazole sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections [see INDICATIONS AND USAGE, Clinical Studies]. Helicobacter Pylori Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology1, and minimum inhibitory concentrations (MICs) were determined. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Incidence Of Antibiotic-Resistant Organisms Among Clinical Isolates Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥1 mcg/mL) to H. pylori was 9% (51/560) at baseline in all treatment groups combined. Greater than 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤0.25 mcg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL. 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 Outcomesa for a Three Drug Regimen (ACIPHEX Delayed-Release Tablets 20 mg Twice Daily, Amoxicillin 1000 mg Twice Daily, and Clarithromycin 500 mg Twice Daily for 7 or 10 Days) Days of RAC Therapy Clarithromycin Pretreatment Results Total Number H. pylori Negative (Eradicated) H. pylori Positive (Persistent) 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 a Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results. b Susceptible (S) MIC ≤0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥1 mcg/mL Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the U.S. multicenter study, greater than 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤0.25 mcg/mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7-and 10-day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy. Pharmacogenomics In a clinical study in evaluating ACIPHEX 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. Clinical Studies Healing Of Erosive Or Ulcerative GERD In Adults In a U.S., multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg, or 40 mg ACIPHEX 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 Week ACIPHEX delayed-release tablets Placebo N=25 10 mg once daily N=27 20 mg once daily N=25 40 mg once daily N=26 4 63%* 56%* 54%* 0% 8 93%* 84%* 85%* 12% * (p<0.001 versus placebo) In addition, there was a statistically significant difference in favor of the ACIPHEX 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 ACIPHEX 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 ACIPHEX 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, the percentage of patients healed at endoscopy after four and eight weeks of treatment was statisticially superior in the patients treated with ACIPHEX delayed-release tablets compared to ranitidine: Table 8: Healing Of Erosive Or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed Week 20 mg ACIPHEX delayed-release tablets once daily N=167 Ranitidine 150 mg four times daily N=169 4 59%* 36% 8 87%* 66% * (p<0.001 versus ranitidine) A dose of 20 mg once daily of ACIPHEX 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<0.001). ACIPHEX 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 ACIPHEX delayed-release tablets is 20 mg once daily for 4 to 8 weeks. Long-Term Maintenance Of Healing Of Erosive Or Ulcerative GERD In Adults 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 ACIPHEX delayed-release tablets once daily or placebo. As demonstrated in Tables 10 and 11 below, patients treated with ACIPHEX 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 ACIPHEX delayed-release tablets is 20 mg once daily. Table 9: Percent of Patients in Endoscopic Remission ACIPHEX delayed-release tablets Placebo 10 mg once daily 20 mg once daily 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% * (p<0.001 versus placebo) Table 10: Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime Heartburn Severity at Week 52 ACIPHEX 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%)† 82/87 (94%)* 67/90 (74%) Nighttime Heartburn Severity Study 1 57/61 (93%)* 60/61 (98%)* 37/56 (66%) Study 2 67/80 (84%) 79/87 (91%)† 64/87 (74%) * p≤0.001 versus placebo † 0.001

Drug Description

Find Lowest Prices on ACIPHEX® SPRINKLE™ (rabeprazole sodium) Delayed-Release Capsules, for Oral Use DESCRIPTION The active ingredient in ACIPHEX Sprinkle delayed-release capsules 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 figure is: ACIPHEX Sprinkle is available for oral administration as 5 mg and 10 mg rabeprazole sodium delayed-release capsules containing enteric coated granules. ACIPHEX Sprinkle contains granules of rabeprazole sodium in a hard hypromellose capsule. Inactive ingredients are colloidal silicon dioxide, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium oxide, magnesium stearate, mannitol, talc, titanium dioxide, carrageenan, potassium chloride, FD&C Blue No. 2 Aluminum Lake (in the 5 mg capsule), FD&C Yellow, No. 6 (in the 10 mg capsule), and gray printing ink.

Drug Description

Find Lowest Prices on ACIPHEX® (rabeprazole sodium) Delayed-Release Tablets DESCRIPTION The active ingredient in ACIPHEX delayed-release tablets is rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2-[[[4-(3methoxypropoxy)-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 figure is: ACIPHEX is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium. Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.

Indications & Dosage

INDICATIONS ACIPHEX Sprinkle is indicated for treatment of Gastroesophageal Reflux Disease (GERD) in pediatric patients 1 to 11 years of age for up to 12 weeks. DOSAGE AND ADMINISTRATION Dosage Regimen ACIPHEX Sprinkle is recommended for up to 12 weeks in pediatric patients 1 to 11 years of age and is dosed by body weight: Less than 15 kg: 5 mg once daily with the option to increase to 10 mg once daily, if inadequate response. 15 kg or more: 10 mg once daily. Administration Recommendations Take the dose 30 minutes before a meal. Do not swallow the capsule whole. Open a capsule and sprinkle entire contents on a small amount of soft food (e.g., applesauce, fruit or vegetable based baby food, or yogurt) or empty contents into a small amount of liquid (e.g., infant formula, apple juice, or pediatric electrolyte solution). Food or liquid should be at or below room temperature. Do not chew or crush the granules. Take the entire dose within 15 minutes of preparation. Do not store mixture for future use. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to the normal schedule. Do not take 2 doses at the same time. HOW SUPPLIED Dosage Forms And Strengths ACIPHEX Sprinkle is provided as: 5 mg: transparent blue and opaque white No. 2 capsule imprinted with “↑” on the capsule cap and “ACX 5mg” on the capsule body. 10 mg: transparent yellow and opaque white No. 2 capsule imprinted with “↑” on the capsule cap and “ACX 10mg” on the capsule body. Storage And Handling ACIPHEX Sprinkle delayed-release capsules (5 mg) are supplied as transparent blue and opaque white capsules containing enteric coated granules. Identification and strength (ACX 5mg) are imprinted on the body of the capsule. An arrow (↑) imprint on the capsule cap indicates direction for opening a capsule. Bottles of 30 (NDC 13551-205-01) ACIPHEX Sprinkle delayed-release capsules (10 mg) are supplied as transparent yellow and opaque white capsules containing enteric coated granules. Identification and strength (ACX 10mg) are imprinted on the body of the capsule. An arrow (↑) imprint on the capsule cap indicates direction for opening a capsule. Bottles of 30 (NDC 13551-210-01) Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Distributed by: Avadel Pharmaceuticals (USA), Inc. Chesterfield, MO 63005. Revised: July 2017

Indications & Dosage

INDICATIONS Healing Of Erosive Or Ulcerative GERD In Adults ACIPHEX 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 ACIPHEX may be considered. Maintenance Of Healing Of Erosive Or Ulcerative GERD In Adults ACIPHEX 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. Treatment Of Symptomatic GERD In Adults ACIPHEX 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. Healing Of Duodenal Ulcers In Adults ACIPHEX 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. Helicobacter Pylori Eradication To Reduce The Risk Of Duodenal Ulcer Recurrence In Adults ACIPHEX delayed-release tablets, in combination with amoxicillin and clarithromycin as a three drug regimen, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [see CLINICAL PHARMACOLOGY and the full prescribing information for clarithromycin]. Treatment Of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome In Adults ACIPHEX delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. Treatment Of Symptomatic GERD In Adolescent Patients 12 Years Of Age And Older ACIPHEX delayed-release tablets are indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks. DOSAGE AND ADMINISTRATION Table 1 shows the recommended dosage of ACIPHEX delayed-release tablets in adults and adolescent patients 12 years of age and older. The use of ACIPHEX 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 ACIPHEX Delayed-Release Tablets in Adults and Adolescents 12 Years of Age and Older Indication Dosage of ACIPHEX delayed-release tablets Treatment Duration Adults Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) 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 beyond 12 months Symptomatic GERD in Adults 20 mg once daily Up to 4 weeks** Up to 4 weeks** 20 mg once daily after the morning meal Up to 4 weeks*** Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence ACIPHEX 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] 7 days Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome Starting dose 60 mg once daily then adjust to patient needs; some patients require divided doses Dosages of 100 mg once daily and 60 mg twice daily have been administered As long as clinically indicated Some patients with Zollinger-Ellison syndrome have been treated continuously for up to one year Adolescents 12 Years of Age and Older Symptomatic GERD 20 mg once daily Up to 8 weeks * For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of ACIPHEX 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. Administration Instructions Swallow ACIPHEX delayed-release tablets whole. Do not chew, crush, or split tablets. For the treatment of duodenal ulcers take ACIPHEX delayed-release tablets after a meal. For Helicobacter pylori eradication take ACIPHEX delayed-release tablets with food. For all other indications ACIPHEX delayed-release tablets can be taken with or without food. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to the normal schedule. Do not take two doses at the same time. HOW SUPPLIED Dosage Forms And Strengths ACIPHEX delayed-release tablets are provided in one strength, 20 mg. The tablets are round, light yellow, enteric coated, biconvex tablets. “ACIPHEX 20” is imprinted in red on one side of the tablet. Storage And Handling ACIPHEX 20 mg is supplied as delayed-release light yellow enteric-coated tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side. Bottles of 30 (NDC 62856-243-30) Bottles of 90 (NDC 62856-243-90) Unit Dose Blisters Package of 100 (10 x 10) (NDC 62856-243-41) Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Distributed by Eisai Inc., Woodcliff Lake, NJ 07677. Revised: Oct 2016

Medication Guide

PATIENT INFORMATION ACIPHEX® Sprinkle™ (a-se-feks spr-en-kle) (rabeprazole sodium) delayed-release capsules What is the most important information I should know about ACIPHEX Sprinkle? Your child should take ACIPHEX Sprinkle exactly as prescribed, at the lowest dose possible and for the shortest time needed. ACIPHEX Sprinkle may help your child’s acid-related symptoms, but your child could still have serious stomach problems. Talk with your child’s doctor. ACIPHEX Sprinkle can cause serious side effects, including: A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including ACIPHEX Sprinkle, may develop a kidney problem called acute interstitial nephritis that can happen at any time during treatment with ACIPHEX Sprinkle. Call your child’s doctor right away if your child has a decrease in the amount that they urinate or if they have blood in their urine. Diarrhea caused by an infection (Clostridium difficile) in your child’s intestines. Call your child’s doctor right away if your child has watery stools or stomach pain that does not go away. Your child may or may not have a fever. Bone fractures (hip, wrist or spine). Bone fractures in the hip, wrist or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your child’s doctor if your child has a bone fracture, especially in the hip, wrist or spine. Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including ACIPHEX Sprinkle, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your child’s doctor right away if they have new or worsening joint pain or a rash on their cheeks or arms that gets worse in the sun. Talk to your child’s doctor about your child’s risk of serious side effects. ACIPHEX Sprinkle can have other serious side effects. See “What are the possible side effects of ACIPHEX Sprinkle?” What is ACIPHEX Sprinkle? ACIPHEX Sprinkle is a prescription medicine called a proton pump inhibitor (PPI). ACIPHEX Sprinkle reduces the amount of acid in the stomach. ACIPHEX Sprinkle is used in children 1 year to 11 years of age to treat Gastroesophageal Reflux Disease (GERD) for up to 12 weeks. ACIPHEX Sprinkle is not effective in treating GERD in children under 1 year of age. ACIPHEX Sprinkle should not be used to treat GERD in babies younger than 1 month of age. Your child should not take ACIPHEX Sprinkle if they are: allergic to rabeprazole, any other PPI medicine, or any of the ingredients in ACIPHEX Sprinkle. See the end of this Medication Guide for a complete list of ingredients. taking a medicine that contains rilpivirine (EDURANT, COMPLERA, ODEFSEY) used to treat HIV1 (Human Immunodeficiency Virus). Before your child takes ACIPHEX Sprinkle, tell your child’s doctor about all of your child’s medical conditions, including if they: have low magnesium levels in their blood. have liver problems. are pregnant or plan to become pregnant. It is not known if ACIPHEX Sprinkle can harm an unborn baby. are breastfeeding or plan to breastfeed. It is not known if ACIPHEX Sprinkle passes into breast milk. Talk to your child’s doctor about the best way to feed her baby if she takes ACIPHEX Sprinkle. Tell your child’s doctor about all the medicines your child takes, including prescription and overthe-counter medicines, vitamins, and herbal supplements. Especially tell your child’s doctor if your child takes warfarin (COUMADIN, JANTOVEN) or methotrexate (Otrexup, Rasuvo,Trexall, Xatmep). How should my child take ACIPHEX Sprinkle? Your child should take ACIPHEX Sprinkle exactly as prescribed. Your child’s doctor will prescribe the dose that is right for your child. Your child should take ACIPHEX Sprinkle 1 time each day. Your child should take ACIPHEX Sprinkle 30 minutes before a meal. Your child should not swallow the ACIPHEX Sprinkle capsule whole. Prepare and give a dose of ACIPHEX Sprinkle to your child as follows: Open the ACIPHEX Sprinkle capsule in the direction that the arrow (↑) on the capsule is pointing. Sprinkle all of the capsule contents onto a small amount of soft food such as applesauce, fruit or vegetable based baby food, or yogurt. You may also empty all of the capsule contents into a small amount of infant formula, apple juice, or a pediatric electrolyte solution. The food or liquid that you use should be at or below room temperature. Your child should swallow the entire mixture. They should not chew or crush the granules. Your child should take the entire dose within 15 minutes of preparing it. Do not save it for use later. If your child misses a dose of ACIPHEX Sprinkle, they should take it as soon as possible. If it is almost time for their next dose, they should not take the missed dose. Your child should take their next dose at their regular time. They should not take 2 doses at the same time. If your child takes too much ACIPHEX Sprinkle, call your child’s doctor or your poison control center at 1-800-222-1222 right away, or go to the nearest emergency room. What are the possible side effects of ACIPHEX Sprinkle? ACIPHEX Sprinkle can cause serious side effects, including: See “What is the most important information I should know about ACIPHEX Sprinkle?” Interaction with warfarin. Taking warfarin with a PPI medicine may lead to an increased risk of bleeding and death. If your child takes warfarin, their doctor may check their blood to see if they have an increased risk of bleeding. If your child takes warfarin during treatment with ACIPHEX Sprinkle, tell their doctor right away if they have any signs or symptoms of bleeding, including: pain, swelling or discomfort menstrual bleeding that is heavier than headaches, dizziness, or weakness normal unusual bruising (bruises that happen without known cause or that grow in o red or black stools size) pink or brown urine coughing up blood nosebleeds vomiting blood or vomit that looks like bleeding gums coffee grounds bleeding from cuts takes a long time to stop Low vitamin B-12 levels in the body can happen in people who have taken ACIPHEX Sprinkle for a long time (more than 3 years). Tell your child’s doctor if your child has symptoms of low vitamin B-12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms and legs. Low magnesium levels in the body can happen in people who have taken ACIPHEX Sprinkle for at least 3 months. Tell your child’s doctor if your child has symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice. The most common side effects of ACIPHEX Sprinkle include: vomiting, stomach-area (abdomen) pain, diarrhea, headache, and nausea. These are not all of the possible side effects of ACIPHEX Sprinkle. Call your child’s doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ACIPHEX Sprinkle? Store ACIPHEX Sprinkle in a dry place at room temperature between 68°F to 77°F (20°C to 25°C). Keep ACIPHEX Sprinkle and all medicines out of the reach of children. General Information about the safe and effective use of ACIPHEX Sprinkle. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ACIPHEX Sprinkle for a condition for which it was not prescribed. Do not give ACIPHEX Sprinkle to other people, even if they have the same symptoms that you have. It may harm them. You can ask your child’s doctor or pharmacist for information about ACIPHEX Sprinkle that is written for health professionals. What are the ingredients in ACIPHEX Sprinkle? Active ingredient: rabeprazole sodium Inactive ingredients: colloidal silicon dioxide, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium oxide, magnesium stearate, mannitol, talc, titanium dioxide, carrageenan, potassium chloride, FD&C Blue No. 2 Aluminum Lake (in the 5 mg capsule), FD&C Yellow, No. 6 (in the 10 mg capsule), and gray printing ink. This Medication Guide has been approved by the U.S. Food and Drug Administration.

Medication Guide

PATIENT INFORMATION ACIPHEX® (a-se-feks) (Rabeprazole Sodium) Delayed-Release Tablets Read the Medication Guide that comes with ACIPHEX 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 ACIPHEX? ACIPHEX may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor. ACIPHEX can cause serious side effects, including: A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including ACIPHEX, may develop a kidney problem called acute interstitial nephritis that can happen at any time during treatment with ACIPHEX. Call your doctor if you have a decrease in the amount that you urinate or if you have blood in your urine. Diarrhea. ACIPHEX may increase your risk of getting severe diarrhea. This diarrhea may be caused by 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 PPI 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 ACIPHEX exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including ACIPHEX, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun. Talk to your doctor about your risk of these serious side effects if you take ACIPHEX. ACIPHEX can have other serious side effects. See “What are the possible side effects of ACIPHEX?” What is ACIPHEX? ACIPHEX is a prescription medicine called a proton pump inhibitor (PPI). ACIPHEX reduces the amount of acid in your stomach. ACIPHEX 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 ACIPHEX. to maintain the healing of the esophagus and relief of symptoms related to EE. It is not known if ACIPHEX is safe and effective if used longer than 12 months (1 year). for up to 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. ACIPHEX is used in adolescents 12 years of age and older to treat symptoms of Gastroesophageal Reflux Disease (GERD) for up to 8 weeks. It is not known if ACIPHEX is safe and effective in children to: heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) maintain the healing of the esophagus and relief of symptoms related to EE treat symptoms that happen with Gastroesophageal Reflux Disease (GERD) heal duodenal ulcers treat an infection caused by bacteria called H. pylori to reduce the risk of duodenal ulcers from coming back treat conditions where your stomach makes too much acid, including Zollinger-Ellison Syndrome. ACIPHEX delayed-release tablets should not be used in children under 12 years of age. Who should not take ACIPHEX? Do not take ACIPHEX if you: are allergic to rabeprazole or any of the other ingredients in ACIPHEX. See the end of this Medication Guide for a complete list of ingredients in ACIPHEX. are allergic to any other proton pump inhibitor (PPI) medicine are taking a medicine that contains rilpivirine (Edurant, Complera) used to treat HIV-1 (Human Immunodeficiency Virus) What should I tell my doctor before taking ACIPHEX? Before you take ACIPHEX 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 plan to become pregnant. It is not known if ACIPHEX can harm your unborn baby. Talk to your doctor about the possible risks to an unborn baby if ACIPHEX is taken during pregnancy. are breastfeeding or plan to breastfeed. It is not known if ACIPHEX passes into your breast milk or if it will affect your baby or your breast milk. Talk to your doctor about the best way to feed your baby if you take ACIPHEX. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ACIPHEX may affect how other medicines work, and other medicines may affect how ACIPHEX works. Especially tell your doctor if you take an antibiotic that contains clarithromycin or amoxicillin or if you take warfarin (COUMADIN, JANTOVEN) or methotrexate (Otrexup, Rasuvo, Trexall). 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 ACIPHEX? Take ACIPHEX 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 ACIPHEX unless you talk to your doctor. Take ACIPHEX for as long as it is prescribed even if you feel better. ACIPHEX is usually taken 1 time each day. Your doctor will tell you the time of day to take ACIPHEX, based on your medical condition. ACIPHEX 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 ACIPHEX tablet whole. Do not chew, crush, or split ACIPHEX tablets. Tell your doctor if you cannot swallow tablets whole. If you miss a dose of ACIPHEX, 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 ACIPHEX, call your doctor or your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room. Your doctor may prescribe antibiotic medicines with ACIPHEX 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 ACIPHEX? ACIPHEX may cause serious side effects, including: See “What is the most important information I should know about ACIPHEX?” Interaction with warfarin. Taking warfarin with a PPI medicine may lead to an increased risk of bleeding and death. If you take warfarin, your doctor may check your blood to see if you have an increased risk of bleeding. If you take warfarin during treatment with ACIPHEX, tell your doctor right away if you have any signs or symptoms of bleeding, including: unexpected bleeding or bleeding that lasts a long time, such as: nosebleeds that happen often unusual bleeding from the gums menstrual bleeding that is heavier than normal or unusual vaginal bleeding bleeding that is severe or that you cannot control red, pink or brown urine bright red or black stools (looks like tar) coughing up blood or blood clots vomiting blood or your vomit looks like “coffee grounds” headaches feel dizzy or weak Vitamin B-12 deficiency. ACIPHEX reduces the amount of acid in your stomach. Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor about the possibility of vitamin B-12 deficiency if you have been on ACIPHEX for a long time (more than 3 years). Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a PPI 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 and get medical care if you have any of these symptoms: seizures dizziness abnormal or fast heart beat jitteriness jerking movements or shaking (tremors) muscle weakness spasms of the hands and feet cramps or muscle aches spasm of the voice box Your doctor may check the level of magnesium in your body before you start taking ACIPHEX, during treatment, or if you will be taking ACIPHEX for a long period of time. The most common side effects of ACIPHEX in adults include: pain sore throat gas infection constipation The most common side effects of ACIPHEX in adolescents 12 years of age and older include: headache diarrhea nausea vomiting stomach-area (abdomen) pain Other side effects: Serious allergic reactions. Tell your doctor if you get any of the following symptoms with ACIPHEX: rash face swelling throat tightness difficulty breathing Your doctor may stop ACIPHEX if these symptoms happen. These are not all of the possible side effects of ACIPHEX. 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 ACIPHEX? Store ACIPHEX Tablets in a dry place at room temperature between 68°F to 77°F (20°C to 25°C). Keep ACIPHEX and all medicines out of the reach of children. General Information about ACIPHEX Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ACIPHEX for a condition for which it was not prescribed. Do not give ACIPHEX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about ACIPHEX that is written for health professionals. What are the ingredients in ACIPHEX? Active ingredient: rabeprazole sodium Inactive ingredients: carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.

Overdosage & Contraindications

Side Effects & Drug Interactions

SIDE EFFECTS The following serious adverse reactions are described below and elsewhere in labeling: Acute Interstitial Nephritis [see WARNINGS AND PRECAUTIONS] Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS] Bone Fracture [see WARNINGS AND PRECAUTIONS] Cutaneous and Systemic Lupus Erythematosus [see WARNINGS AND PRECAUTIONS] Cyanocobalamin (Vitamin B-12) Deficiency [see WARNINGS AND PRECAUTIONS] Hypomagnesemia [see WARNINGS AND PRECAUTIONS] 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. The efficacy of ACIPHEX Sprinkle was established in a two-part, randomized, multicenter, double-blind, parallel-group study of 127 pediatric patients 1 to 11 years of age with a history of at least one GERD symptom within the 3 months before screening and a positive esophagogastroduodenoscopy (EGD; Hetzel-Dent Endoscopic Classification System, Grade ≥1 and Histological Features of Reflux Esophagitis Scale, Grade >0). The two-part study consisted of a 12-week treatment period in patients with endoscopically-proven GERD followed by a 24week, double-blinded extension study. Subjects had a mean age of 6 years (range: 1 to 11 years) and 44% (56/127) were female and 56% (71/127) were male. Of the 127 subjects enrolled, 78% (99/127) were white, 10% (13/127) were black, and 2% (3/127) were Asian. In the study, patients less than 15 kg body weight received either 5 mg or 10 mg ACIPHEX Sprinkle and patients 15 kg or greater body weight received 10 mg ACIPHEX Sprinkle. In this study, some patients were treated for 36 weeks. The most common adverse reactions leading to discontinuation were vomiting, abdominal pain, diarrhea, and nausea. The most common adverse reactions from the first 12 weeks of treatment are listed in Table 1. Table 1: Common Adverse Reactions* in Pediatric Study (Ages 1 To 11 Years First 12 Weeks of Treatment) Adverse Reaction Patients Less than 15 kg Patients 15 kg or greater 5 mg (N=21) % 10 mg (N=19) % 10 mg (N=44) % Vomiting 10 11 14 Abdominal Pain 0 0 16 Diarrhea 14 21 9 Headache 0 0 9 Nausea 0 0 9 * incidence of adverse reactions ≥9% The safety profile was similar for those patients who received treatment for up to 36 weeks. Adults And Adolescents Experience With Other Rabeprazole Formulations 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. An analysis of adverse reactions appearing in ≥2% of rabeprazole-treated 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%). Other adverse reactions seen in controlled clinical trials, which do not meet the above criteria (≥2% of rabeprazole-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. 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 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. Postmarketing Experience The following adverse reactions have been identified during post approval use of rabeprazole sodium. 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, and thrombocytopenia Ear and Labyrinth Disorders: vertigo Eye Disorders: blurred vision 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) 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 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 DRUG INTERACTIONS Table 2 includes clinically important drug interactions and interaction with diagnostics when administered concomitantly with ACIPHEX Sprinkle 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 ACIPHEX Sprinkle and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs 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, 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 ACIPHEX Sprinkle is contraindicated [see CONTRAINDICATIONS]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with ACIPHEX Sprinkle. 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]. 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]. Intervention: A temporary withdrawal of ACIPHEX Sprinkle may be considered in some patients receiving high-dose methotrexate administration. Digoxin Clinical Impact: Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY]. 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 ACIPHEX Sprinkle and MMF. Use ACIPHEX Sprinkle with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. 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 ACIPHEX Sprinkle 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 adults in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention: Temporarily stop treatment with ACIPHEX 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.

Side Effects & Drug Interactions

SIDE EFFECTS The following serious adverse reactions are described below and elsewhere in labeling: Acute Interstitial Nephritis [see WARNINGS AND PRECAUTIONS] Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS] Bone Fracture [see WARNINGS AND PRECAUTIONS] Cutaneous and Systemic Lupus Erythematosus [see WARNINGS AND PRECAUTIONS] Cyanocobalamin (Vitamin B-12) Deficiency [see WARNINGS AND PRECAUTIONS] Hypomagnesemia [see WARNINGS AND PRECAUTIONS] 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 ACIPHEX 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 ACIPHEX delayed-release tablets. An analysis of adverse reactions appearing in ≥2% of patients treated with ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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. Postmarketing Experience The following adverse reactions have been identified during post approval use of rabeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sudden death; coma; hyperammonemia; jaundice; rhabdomyolysis; disorientation 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-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. DRUG INTERACTIONS Table 2 includes drugs with clinically important drug interactions when administered concomitantly with ACIPHEX 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 ACIPHEX 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. 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 ACIPHEX delayed-release tablets is contraindicated [see CONTRAINDICATIONS]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with ACIPHEX 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]. 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]. Intervention: A temporary withdrawal of ACIPHEX 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]. 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 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 PPIs and MMF. Use ACIPHEX 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 Intervention: information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.

Warnings & Precautions

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Presence Of Gastric Malignancy In adults, symptomatic response to therapy with ACIPHEX 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. In older patients, also consider an endoscopy. 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 ACIPHEX Sprinkle and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time [see DRUG INTERACTIONS]. Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including rabeprazole sodium. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue ACIPHEX Sprinkle if acute interstitial nephritis develops [see CONTRAINDICATIONS]. Clostridium Difficile-Associated Diarrhea Published observational studies suggest that PPI therapy like ACIPHEX Sprinkle 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]. 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. 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, ADVERSE REACTIONS]. ACIPHEX Sprinkle is indicated for short-term treatment up to 12 weeks. Treatment for longer than 12 weeks is not recommended. 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 ACIPHEX Sprinkle, 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. 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 ACIPHEX Sprinkle. Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in adult 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]. ACIPHEX Sprinkle is indicated for short-term treatment of up to 12 weeks. Treatment for longer than 12 weeks is not recommended. Interaction With Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see DRUG INTERACTIONS]. Patient Counseling Information Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Acute Interstitial Nephritis Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute interstitial nephritis [see WARNINGS AND PRECAUTIONS]. Clostridium Difficile-Associated Diarrhea Advise the patient or caregiver to immediately call the patient’s healthcare provider if they experience diarrhea that does not improve [see WARNINGS AND PRECAUTIONS]. Bone Fracture Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient’s healthcare provider [see WARNINGS AND PRECAUTIONS]. Cutaneous And Systemic Lupus Erythematosus Advise the patient or caregiver to immediately call the patient’s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see WARNINGS AND PRECAUTIONS] Cyanocobalamin (Vitamin B-12) Deficiency Advise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient’s healthcare provider if they have been receiving ACIPHEX Sprinkle for longer than 3 years [see WARNINGS AND PRECAUTIONS]. Hypomagnesemia Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia to the patient’s healthcare provider, if they have been receiving ACIPHEX Sprinkle for at least 3 months [see WARNINGS AND PRECAUTIONS]. Drug Interactions Advise the patient or caregiver to report to the patient’s healthcare provider if they are taking rilpilvirine-containing products [see CONTRAINDICATIONS], warfarin or high-dose methotrexate [see WARNINGS AND PRECAUTIONS]. Administration Take the dose 30 minutes before a meal. Do not swallow the capsule whole. Open the ACIPHEX Sprinkle capsule and sprinkle the granule contents on a small amount of soft food (e.g., applesauce, fruit or vegetable based baby food, or yogurt) or empty contents into a small amount of liquid (e.g., infant formula, apple juice, or pediatric electrolyte solution). Food or liquid should be at or below room temperature. Do not chew or crush the granules. Take the entire dose within 15 minutes of preparation. Do not store mixture for future use. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to the normal schedule. Do not take 2 doses at the same time. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility In an 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 adult human exposure (plasma AUC0-∞ = 0.88 μg•hr/mL) at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per 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 to 24 times the adult human exposure at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). 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 adult human exposure at the recommended dose for GERD (20 mg of rabeprazole sodium delayed-release tablets per day). 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 adult 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 adult human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats. The recommended dose for GERD in adults is 20 mg per day (rabeprazole sodium delayed-release tablets). Use In Specific Populations Pregnancy Risk Summary There are no available human data on ACIPHEX 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.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% 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. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data]. Data Animal Data Embryo-fetal developmental studies have been performed in rats at intravenous doses of rabeprazole during organogenesis up to 50 mg/kg/day (plasma AUC of 11.8 μg•hr/mL, about 13 times the adult 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 μg•hr/mL, about 8 times the adult human exposure at the recommended oral dose for GERD: 20 mg of rabeprazole delayed-release tablets per day) 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 adult human oral dose based on mg/m2) resulted in decreases in body weight gain of the pups. 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 3.4 to 57 times an oral human dose on a body surface area basis. 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 33.6 times an oral human dose on a body surface area basis. A follow-up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with a different PPI at oral doses of 280 mg/kg/day (about 68 times an oral human dose on a body surface area basis) where drug administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. Lactation 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 ACIPHEX Sprinkle and any potential adverse effects on the breastfed infant from ACIPHEX Sprinkle or from the underlying maternal condition. Pediatric Use GERD In Pediatric Patients 1 To 11 Years Of Age The use of ACIPHEX Sprinkle for treatment of GERD in pediatric patients 1 to 11 years of age is supported by a randomized, multicenter, double-blind clinical trial which evaluated two dose levels of ACIPHEX Sprinkle in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment. Dosing was determined by body weight: Patients weighing 6.0 to 14.9 kg received either 5 or 10 mg of ACIPHEX Sprinkle daily and those weighing 15.0 kg or more received 10 or 20 mg of ACIPHEX Sprinkle daily. After 12 weeks of rabeprazole treatment, 81% of patients demonstrated esophageal mucosal healing on endoscopic assessment. In patients who had esophageal mucosal healing at 12 weeks and elected to continue for 24 more weeks of rabeprazole, 90% retained esophageal mucosal healing at 36 weeks. No prespecified formal hypothesis testing for evaluation of efficacy was conducted. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. There were no adverse reactions reported in this study that were not previously observed in adolescents or adults. Symptomatic GERD in Infants 1 to 11 Months of Age The use of ACIPHEX Sprinkle is not recommended because studies conducted do not demonstrate efficacy for the treatment of GERD in pediatric patients younger than 1 year of age. In a randomized, multicenter, placebo-controlled withdrawal trial, infants 1 to 11 months of age with a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD, were treated up to 8 weeks in two treatment periods. In the first treatment period (open-label), 344 infants received 10 mg of ACIPHEX Sprinkle for up to 3 weeks. Infants with clinical response were then eligible to enter the second treatment period, which was double-blind and randomized. Two hundred sixty-eight infants were randomized to receive either placebo or 5 mg or 10 mg ACIPHEX Sprinkle. This study did not demonstrate efficacy based on assessment of frequency of regurgitation and weight-for-age Z-score. Adverse reactions that occurred in ≥5% of patients in any treatment group and with a higher rate than placebo included pyrexia (7%) and increased serum gastrin levels (5%). There were no adverse reactions reported in this study that were not previously observed in adolescents and adults. Neonates <1 Month And Preterm Infants <44 Weeks Corrected Gestational Age The use of ACIPHEX Sprinkle is not recommended for the treatment of GERD, based on the risk of prolonged acid suppression and lack of demonstrated safety and effectiveness in neonates. Based on population pharmacokinetic analysis, the median (range) for the apparent clearance (CL/F) was 1.05 L/h (0.0543 to 3.44 L/h) in neonates and 4.46 L/h (0.822 to 12.4 L/h) in patients 1 to 11 months of age following once daily administration of oral ACIPHEX Sprinkle. 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. Geriatric Use No studies with ACIPHEX Sprinkle have been conducted in geriatric patients. ACIPHEX Sprinkle is not indicated for use in patients older than 11 years of age. Hepatic Impairment Administration of rabeprazole sodium delayed-release tablets to adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) resulted in increased exposure and decreased elimination [see CLINICAL PHARMACOLOGY]. No dosage adjustment of ACIPHEX Sprinkle is necessary in patients with mild to moderate hepatic impairment. There is no information in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of ACIPHEX Sprinkle in patients with severe hepatic impairment; however, if treatment is necessary, monitor patients for adverse reactions [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Warnings & Precautions

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Presence Of Gastric Malignancy In adults, symptomatic response to therapy with ACIPHEX 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. 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 ACIPHEX delayed-release tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time [see DRUG INTERACTIONS]. Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including ACIPHEX. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue ACIPHEX if acute interstitial nephritis develops [see CONTRAINDICATIONS]. Clostridium Difficile-Associated Diarrhea Published observational studies suggest that PPI therapy like ACIPHEX 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]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with ACIPHEX, refer to Warnings and Precautions sections of the corresponding prescribing information. 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, ADVERSE REACTIONS]. 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 ACIPHEX, 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. 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 ACIPHEX. Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see ADVERSE REACTIONS]. Interaction With Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum concentrations 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]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Adverse Reactions Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with: Hypersensitivity Reactions [see CONTRAINDICATIONS]. Acute Interstitial Nephritis [see WARNINGS AND PRECAUTIONS]. Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS]. Bone Fracture [see WARNINGS AND PRECAUTIONS]. Cutaneous and Systemic Lupus Erythematosus [see WARNINGS AND PRECAUTIONS]. Cyanocobalamin (Vitamin B-12) Deficiency [see WARNINGS AND PRECAUTIONS]. Hypomagnesemia [see WARNINGS AND PRECAUTIONS]. Drug Interactions Advise patients to report to their healthcare provider if they are taking warfarin or high-dose methotrexate [see WARNINGS AND PRECAUTIONS]. Administration Swallow ACIPHEX delayed-release tablets whole. Do not chew, crush or split the tablets. For the treatment of duodenal ulcers take ACIPHEX delayed-release tablets after a meal. For Helicobacter pylori eradication take ACIPHEX delayed-release tablets with food. For all other indications ACIPHEX delayed-release tablets can be taken with or without food. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to the normal schedule. Do not take two doses at the same time. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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 AUC0-∞ = 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 to 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. Use In Specific Populations Pregnancy Risk Summary There are no available human data on ACIPHEX 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.S. 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 [see Data]. Advise pregnant women of the potential risk to a fetus. 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 μg•hr/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 μg•hr/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/m2) resulted in decreases in body weight gain of the pups. 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 3.4 to 57 times an oral human dose on a body surface area basis. 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 33.6 times an oral human dose on a body surface area basis. Lactation 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 ACIPHEX and any potential adverse effects on the breastfed infant from ACIPHEX or from the underlying maternal condition. Pediatric Use The safety and effectiveness of ACIPHEX 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 ACIPHEX 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 ACIPHEX delayed-release tablets have not been established in pediatric patients for: Healing of Erosive or Ulcerative GERD Maintenance of Healing of Erosive or Ulcerative GERD Treatment of Symptomatic GERD Healing of Duodenal Ulcers Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ACIPHEX 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]. For pediatric patients 1 year to less than 12 years of age consider another rabeprazole formulation. The safety and effectiveness of a different dosage form and dosage strength of rabeprazole has been established in pediatric patients 1 to 11 years for the treatment of GERD. 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. Geriatric Use Of the total number of subjects (n=2009) in clinical studies of ACIPHEX 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. Hepatic Impairment Administration of ACIPHEX 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]. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no information in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of ACIPHEX delayed-release tablets in patients with severe hepatic impairment; however, if treatment is necessary, monitor patients for adverse reactions [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].