RABEPRAZOLE SODIUM

The active ingredient in Rabeprazole Sodium Delayed-Release Tablets is rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1 H- benzimidazole sodium salt. It has an empirical formula of C 18 H 20 N 3 NaO 3 S and a molecular weight of 381.42. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural formula is: FIGURE 1 Rabeprazole Sodium Delayed-Release Tablets is available for oral administration as Delayed-Release, enteric-coated tablets containing 20 mg of rabeprazole sodium. Inactive ingredients of the 20 mg tablet are crospovidone, FD&C Blue #1, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, talc and triethyl citrate. Figure 1

Rabeprazole Sodium Delayed-Release Tablets is a proton pump inhibitor (PPI) indicated in adults for: • Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)( 1.1 ) • Maintenance of Healing of Erosive or Ulcerative GERD ( 1.2 ) • Treatment of Symptomatic GERD ( 1.3 ) • Healing of Duodenal Ulcers ( 1.4 ) • Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence ( 1.5 ) • Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ( 1.6 ) In adolescent patients 12 years of age and older for: • Short-term treatment of Symptomatic GERD ( 1.7 ) 1.1 Healing of Erosive or Ulcerative GERD in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole Sodium Delayed-Release Tablets may be considered. 1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months. 1.3 Treatment of Symptomatic GERD in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults. 1.4 Healing of Duodenal Ulcers in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks. 1.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults Rabeprazole Sodium Delayed-Release Tablets in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori . Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [ see Clinical Studies (14.5) and Dosage and Administration (2.5) ]. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [ see Clinical Pharmacology (12.2) and the clarithromycin package insert, Clinical Pharmacology (12.2) ]. 1.6 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults Rabeprazole Sodium Delayed-Release Tablets is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome. 1.7 Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older Rabeprazole Sodium Delayed-Release Tablets is indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.

Rabeprazole Sodium Delayed-Release Tablets should be swallowed whole. The tablets should not be chewed, crushed, or split ( 2.10 ). Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) ( 2.1 ) 20 mg once daily Maintenance of Healing of Erosive or Ulcerative GERD ( 2.2 ) 20 mg once daily Treatment of Symptomatic GERD in Adults ( 2.3 ) 20 mg once daily Healing of Duodenal Ulcers ( 2.4 ) 20 mg once daily after morning meal Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence ( 2.5 ) Three Drug Regimen: Rabeprazole Sodium Delayed-Release Tablets 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg All three medications should be taken twice daily with morning and evening meals for 7 days Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ( 2.6 ) Starting dose 60 mg once daily then adjust to patient needs Treatment of Symptomatic GERD in Adolescents 12 Years of Age and Older ( 2.7 ) 20 mg once daily 2.1 Healing of Erosive or Ulcerative GERD in Adults The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for four to eight weeks [ see Indications and Usage (1.1) ]. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole Sodium Delayed-Release Tablets may be considered. 2.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily [ see Indications and Usage (1.2) ]. 2.3 Treatment of Symptomatic GERD in Adults The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for 4 weeks [ see Indications and Usage (1.3) ]. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. The recommended adolescent dosing is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily for 8 weeks. 2.4 Healing of Duodenal Ulcers in Adults The recommended adult oral dose is one Rabeprazole Sodium 20 mg Delayed-Release Tablet to be taken once daily after the morning meal for a period up to four weeks [ see Indications and Usage (1.4) ]. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing. 2.5 Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults TABLE 1 THREE DRUG REGIMEN It is important that patients comply with the full 7-day regimen [ see Clinical Studies (14.5) ]. All three medications should be taken twice daily with the morning and evening meals. Rabeprazole Sodium Delayed-Release Tablet 20 mg Twice Daily for 7 Days Amoxicillin 1000 mg Twice Daily for 7 Days Clarithromycin 500 mg Twice Daily for 7 Days 2.6 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults The dosage of Rabeprazole Sodium Delayed-Release Tablets in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with Rabeprazole Sodium Delayed-Release Tablets for up to one year. 2.7 Short-term Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older The recommended oral dose for adolescents 12 years of age and older is one 20 mg Delayed-Release Tablet once daily for up to 8 weeks [ see Use in Specific Populations (8.4) and Clinical Studies (14.7) ]. 2.9 Elderly, Renal and Hepatic Impaired Patients No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients. 2.10 Administration Recommendations TABLE 2 Administration Recommendations Formulation Population Instructions Delayed-Release Tablet Adults and adolescents 12 years of age and older Swallow tablets whole. Do not chew, crush or split tablets. Tablets can be taken with or without food.

Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with Rabeprazole Sodium Delayed-Release Tablets, refer to the Contraindications section of their package inserts. • History of hypersensitivity to rabeprazole ( 4 )

Worldwide, over 2900 patients have been treated with rabeprazole in Phase II-III clinical trials involving various dosages and durations of treatment. Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. • In the adult studies (4 to 8 weeks), adverse reactions that occurred at a rate greater than 2% and greater than placebo included pain, pharyngitis, flatulence, infection and constipation ( 6.1 ). • In studies of adolescent patients (ages 12 to 16 years, and up to 36 weeks exposure) adverse reactions that occurred at a rate of ≥5% of patients included abdominal pain, diarrhea and headache ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-866-822-0068 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Adults The data described below reflect exposure to Rabeprazole Sodium Delayed-Release Tablets in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in adult patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male: 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian and 5% other. Most patients received either 10 mg, 20 mg or 40 mg/day of Rabeprazole Sodium Delayed-Release Tablets. An analysis of adverse reactions appearing in ³ 2% of Rabeprazole Sodium Delayed-Release Tablet patients (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%). Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to rabeprazole for 6 months while at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of Rabeprazole Sodium Delayed-Release Tablets, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole. The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies. Other adverse reactions that were seen in controlled clinical trials, which do not meet the above criteria (≥ 2% of Rabeprazole Sodium Delayed-Release Tablets treated patients and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia. 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 package prescribing information, Adverse Reactions section. Pediatric In a multicenter, open-label study of adolescent patients aged 12 to 16 years with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to Rabeprazole Sodium Delayed-Release Tablets that occurred in ≥ 2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Rabeprazole Sodium Delayed-Release Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sudden death; coma, hyperammonemia; jaundice; rhabdomyolysis; disorientation and delirium; anaphylaxis; angioedema; bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; interstitial pneumonia; interstitial nephritis; TSH elevations, bone fractures, hypomagnesemia and Clostridium difficile associated diarrhea. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported. Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.

• Increased INR and prothrombin times have been reported with concomitant use with warfarin. Patients need to be monitored ( 7.2 ) • Rabeprazole has been shown to inhibit cyclosporine metabolism in vitro ( 7.3 ) • Rabeprazole Sodium Delayed-Release Tablets inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, iron salts and digoxin) ( 7.4 ) • Rabeprazole Sodium Delayed-Release Tablets may reduce the plasma levels of atazanavir ( 7.4 ) • Methotrexate: Rabeprazole Sodium Delayed-Release Tablets may increase serum level of methotrexate ( 7.7 ) 7.1 Drugs Metabolized by CYP450 Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients. 7.2 Warfarin There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [ see Warnings and Precautions (5.2) ]. 7.3 Cyclosporine In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC 50 of 62 micromolar, a concentration that is over 50 times higher than the C max in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations. 7.4 Compounds Dependent on Gastric pH for Absorption Rabeprazole produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with rabeprazole. For example, in normal subjects, co-administration of rabeprazole 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and C max for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma rabeprazole concentrations. Concomitant use of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect. 7.5 Drugs Metabolized by CYP2C19 In a clinical study in Japan evaluating rabeprazole in adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied. 7.6 Combined Administration with Clarithromycin Combined administration consisting of rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin [ see Clinical Pharmacology (12.3) ]. Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [ see Warnings and Precautions in prescribing information for clarithromycin ]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [ see Contraindications in prescribing information for clarithromycin ] [ see Drug Interactions in prescribing information for amoxicillin ]. 7.7 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information ) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [ see Warnings and Precautions (5.6) ]. 7.8 Clopidogrel Concomitant administration of rabeprazole and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel [ see Clinical Pharmacology (12.3) ]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Rabeprazole Sodium Delayed-Release Tablets.

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