PRINCIPAL DISPLAY PANEL - 20 mg Bottle Label

NDC 62175-302-32

Rabeprazole Sodium
Delayed-Release
Tablets

20 mg

Print Medication Guides at: www.lannett.com/med- guide/rabeprazole

Rx Only

30 Tablets

Lannett


1 INDICATIONS AND USAGE

1.1 Healing of Erosive or Ulcerative GERD in Adults

Rabeprazole Sodium Delayed-Release Tablets are indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole Sodium Delayed-Release Tablets may be considered.

1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults

Rabeprazole Sodium Delayed-Release Tablets are indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.

1.3 Treatment of Symptomatic GERD in Adults

Rabeprazole Sodium Delayed-Release Tablets are indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks.

1.4 Healing of Duodenal Ulcers in Adults

Rabeprazole Sodium Delayed-Release Tablets are indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.

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, 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 (12.2) and the full prescribing information for clarithromycin].

1.6 Treatment of Pathological Hypersecretory Conditions, Including

Zollinger-Ellison Syndrome in Adults

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

1.7 Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age

and Older

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

5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with Rabeprazole Sodium Delayed- Release Tablets does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI.

5.2 Interaction with Warfarin

Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with Rabeprazole Sodium Delayed- Release Tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time [see Drug Interactions (7)].

5.3 Acute Tubulointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue Rabeprazole Sodium Delayed-Release Tablets and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.4 Clostridium difficile-Associated Diarrhea

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

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

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

5.5 Bone Fracture

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

5.6 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue Rabeprazole Sodium Delayed-Release Tablets at first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.7 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including rabeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving Rabeprazole Sodium Delayed-Release Tablets, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.8 Cyanocobalamin (Vitamin B-12) Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with Rabeprazole Sodium Delayed-Release Tablets.

5.9 Hypomagnesemia and Mineral Metabolism

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

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

Consider monitoring magnesium and calcium levels prior to initiation of Rabeprazole Sodium Delayed-Release Tablets and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.10 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 (7)].

5.11 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

11 DESCRIPTION

The active ingredient in Rabeprazole Sodium Delayed-Release Tablets is rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium salt. It has an empirical formula of C18H20N3NaO3S and a molecular weight of 381.42. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural figure is:

Rabeprazole Sodium Delayed-Release Tablets are 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 dibehenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, talc and triethyl citrate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.

In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

12.2 Pharmacodynamics

Antisecretory Activity

The antisecretory effect begins within one hour after oral administration of 20 mg Rabeprazole Sodium Delayed-Release Tablets. The median inhibitory effect of rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose. A 20 mg dose of Rabeprazole Sodium Delayed-Release Tablets inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1 to 2 hours) reflects the sustained inactivation of the H+, K+ATPase.

**Table 3: Gastric Acid Parameters: Rabeprazole Sodium Delayed-Release Tablets **versus Placebo After 7 Days of Once Daily Dosing

Compared to placebo, 10 mg, 20 mg, and 40 mg of Rabeprazole Sodium Delayed- Release Tablets, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.

Table 4: AUC Acidity (Mmol•Hr/L):Rabeprazole Sodium Delayed-Release Tabletsversus Placebo on Day 7 of Once Daily Dosing (Mean±SD)

After administration of 20 mg Rabeprazole Sodium Delayed-Release Tablets once daily for eight days, the mean percent of time that gastric pH greater than 3 or gastric pH greater than 4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg Rabeprazole Sodium Delayed-Release Tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:

Table 5: Gastric Acid Parameters****Rabeprazole Sodium Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8

Effects on Esophageal Acid Exposure

In patients with GERD and moderate to severe esophageal acid exposure, a dose of 20 mg and 40 mg per day of Rabeprazole Sodium Delayed-Release Tablets decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that the esophageal pH was less than 4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH greater than 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving Rabeprazole Sodium Delayed-Release Tablets 20 mg and in 100% of subjects receiving Rabeprazole Sodium Delayed-Release Tablets 40 mg. With Rabeprazole Sodium Delayed-Release Tablets 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.

Effects on Serum Gastrin

The median fasting gastrin level increased in a dose-related manner in patients treated once daily with Rabeprazole Sodium Delayed-Release Tablets for up to eight weeks for ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease. The group median values stayed within the normal range.

In a group of subjects treated with 20 mg Rabeprazole Sodium Delayed-Release Tablets for 4 weeks a doubling of mean serum gastrin concentrations was observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal.

Effects on Enterochromaffin-like (ECL) Cells

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females [see Nonclinical Toxicology (13.1)].

In over 400 patients treated with Rabeprazole Sodium Delayed-Release Tablets (10 or 20 mg) once daily for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.

Endocrine Effects

Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male subjects treated with Rabeprazole Sodium Delayed-Release Tablets for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.

Other Effects

In humans treated with Rabeprazole Sodium Delayed-Release Tablets for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with Rabeprazole Sodium Delayed-Release Tablets and ocular effects.

12.3 Pharmacokinetics

After oral administration of 20 mg Rabeprazole Sodium Delayed-Release Tablets, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2 to 5 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole is not altered by multiple dosing.

Absorption

Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When Rabeprazole Sodium Delayed-Release Tablets are administered with a high fat meal, 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 Rabeprazole Sodium 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

Geriatric Patients: In 20 healthy elderly subjects administered 20 mg Rabeprazole Sodium 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 Population (8.5)].

Pediatric Patients: The pharmacokinetics of rabeprazole was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received 20 mg Rabeprazole Sodium Delayed-Release Tablets once daily for five or seven days. An approximate 40% increase in rabeprazole exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult subjects.

Male and Female Patients and Racial or Ethnic Groups: 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.

Patients with 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 Rabeprazole Sodium Delayed-Release Tablets when compared to 10 healthy subjects.

Patients with Hepatic Impairment: In a single dose study of 10 patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a single 20 mg dose of Rabeprazole Sodium Delayed- Release Tablets, 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 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 (8.6)].

Drug Interaction Studies

Combined Administration with Antimicrobials: Sixteen healthy subjects genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg Rabeprazole Sodium Delayed-Release Tablets, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and 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 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 subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as theophylline (CYP1A2) given as single oral doses, diazepam (CYP2C9 and CYP3A4) as a single intravenous dose, and phenytoin (CYP2C9 and CYP2C19) given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.

Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with 20 mg Rabeprazole Sodium Delayed- Release Tablets (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when Rabeprazole Sodium Delayed-Release Tablets were coadministered compared to administration of clopidogrel with placebo [see Drug Interactions (7)].

Digoxin: In healthy adult subjects (n=16), co-administration of 20 mg rabeprazole sodium delayed-release tablets with 2.5 mg once daily doses of digoxin at steady state resulted in approximately 29% and 19% increase in mean Cmax and AUC(0-24) of digoxin [see Drug Interactions (7)].

Ketoconazole: In healthy adult subjects (n=19), co-administration of 20 mg rabeprazole sodium delayed-release tablets at steady state with a single 400 mg oral dose ketoconazole resulted in approximately an average of 31% reduction in both Cmax and AUC(0-inf) of ketoconazole [see Drug Interactions (7)].

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 Rabeprazole Sodium Delayed-Release Tablets. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

12.4 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 (1), Clinical Studies (14.5)].

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 Outcomesafor a Three Drug Regimen (Rabeprazole Sodium Delayed-Release Tablets 20 mg Twice Daily, Amoxicillin 1000 mg Twice Daily, and Clarithromycin 500 mg Twice Daily for 7 or 10 Days)

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.

12.5 Pharmacogenomics

In a clinical study in evaluating Rabeprazole Sodium Delayed-Release Tablets in Japanese adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. The clinical relevance of this is not known. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

All brand names are the trademarks of their respective owners.

Dispense with Medication Guide available at: www.lannett.com/med- guide/rabeprazole

CIA76374P

Rev. 07/2023

13 NONCLINICAL TOXICOLOGY

13.1 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 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.

14 CLINICAL STUDIES

14.1 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 Rabeprazole Sodium Delayed-Release Tablets once daily. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows:

**Table 7: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease **(GERD) Percentage of Patients Healed

In addition, there was a statistically significant difference in favor of the Rabeprazole Sodium Delayed-Release Tablets 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p≤0.026). All Rabeprazole Sodium Delayed-Release Tablets groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p≤0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all Rabeprazole Sodium Delayed-Release Tablets groups when compared to placebo at both Weeks 4 and 8 (p≤0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, the percentage of patients healed at endoscopy after four and eight weeks of treatment was statistically superior in the patients treated with Rabeprazole Sodium Delayed-Release Tablets compared to ranitidine:

**Table 8: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease **(GERD) Percentage of Patients Healed

A dose of 20 mg once daily of Rabeprazole Sodium Delayed-Release Tablets was significantly more effective than ranitidine 150 mg four times daily in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). Rabeprazole Sodium Delayed-Release Tablets were also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

The recommended dosage of Rabeprazole Sodium Delayed-Release Tablets is 20 mg once daily for 4 to 8 weeks.

14.3 Treatment of Symptomatic GERD in Adults

Two U.S., multicenter, double-blind, placebo controlled studies were conducted in 316 adult patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.

The percentage of heartburn free daytime and/or nighttime periods was greater with 20 mg Rabeprazole Sodium Delayed-Release Tablets compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for Rabeprazole Sodium Delayed- Release Tablets 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.

Figure 2: Mean Daytime Heartburn Scores RAB-USA-2


Figure 3: Mean Nighttime Heartburn Scores RAB-USA-2


Figure 4: Mean Daytime Heartburn Scores RAB-USA-3


** Figure 5: Mean Nighttime Heartburn Scores RAB-USA-3**


In addition, the combined analysis of these two studies showed 20 mg of Rabeprazole Sodium Delayed-Release Tablets significantly improved other GERD- associated symptoms (regurgitation, belching, and early satiety) by week 4 compared with placebo (all p values <0.005).

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

The recommended dosage of Rabeprazole Sodium Delayed-Release Tablets is 20 mg once daily for 4 weeks.

14.2 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 Rabeprazole Sodium Delayed-Release Tablets once daily or placebo. As demonstrated in Tables 10 and 11 below, patients treated with Rabeprazole Sodium Delayed-Release Tablets were significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks. The recommended dosage of Rabeprazole Sodium Delayed-Release Tablets is 20 mg once daily.

Table 9: Percent of Patients in Endoscopic Remission

Table 10: Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime Heartburn Severity at Week 52****

14.4 Healing of Duodenal Ulcers in Adults

In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Rabeprazole Sodium Delayed-Release Tablets once daily versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabeprazole Sodium Delayed- Release Tablets were significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

Table 11: Healing of Duodenal Ulcers Percentage of Patients Healed

At Weeks 2 and 4, significantly more patients in the Rabeprazole Sodium Delayed-Release Tablets 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both Rabeprazole Sodium Delayed-Release Tablets groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both Rabeprazole Sodium Delayed- Release Tablets groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg Rabeprazole Sodium Delayed-Release Tablets once daily with 20 mg omeprazole once daily. The study was designed to provide at least 80% power to exclude a difference of at least 10% between Rabeprazole Sodium Delayed-Release Tablets and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, Rabeprazole Sodium Delayed-Release Tablets were comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

Table 12: Healing of Duodenal Ulcers Percentage of Patients Healed

Rabeprazole Sodium Delayed-Release Tablets and omeprazole were comparable in providing complete resolution of symptoms.

The recommended dosage of Rabeprazole Sodium Delayed-Release Tablets is 20 mg once daily for 4 weeks.

14.5 Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease

or Symptomatic Non-Ulcer Disease in Adults

The U.S. multicenter study was a double-blind, parallel-group comparison of Rabeprazole Sodium Delayed-Release Tablets, amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin, and clarithromycin for 10 days. Therapy consisted of rabeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative 13C-UBT for H. pylori ≥6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per- Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

Table 13:Helicobacter pyloriEradication at≥6 Weeks After the End of Treatment

The recommended dosage of Rabeprazole Sodium Delayed-Release Tablets is 20 mg twice daily with amoxicillin and clarithromycin for 7 days.

14.6 Pathological Hypersecretory Conditions, Including Zollinger-Ellison

Syndrome in Adults

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

The recommended starting dosage of Rabeprazole Sodium Delayed-Release Tablets is 60 mg once daily.

16 HOW SUPPLIED/STORAGE AND HANDLING

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

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Acute Tubulointerstitial Nephritis

Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions (5.3)].

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 (5.4)].

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 (5.5)].

Severe Cutaneous Adverse Reactions

Advise the patient or caregiver to discontinue Rabeprazole Sodium Delayed- Release Tablets and report any signs and symptoms of a severe cutaneous adverse reaction or other sign of hypersensitivity to the healthcare provider [see Warnings and Precautions (5.6)].

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 (5.7)].

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 Rabeprazole Sodium Delayed-Release Tablets for longer than 3 years [see Warnings and Precautions (5.8)].

Hypomagnesemia and Mineral Metabolism

Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, hypokalemia and hyponatremia to the patient’s healthcare provider, if they have been receiving Rabeprazole Sodium Delayed-Release Tablets for at least 3 months [see Warnings and Precautions (5.9)].

Drug Interactions

Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products [see Contraindications (4)], warfarin, digoxin or high-dose methotrexate [see Warnings and Precautions (5.2, 5.9, 5.10)].

Administration

• Swallow Rabeprazole Sodium Delayed-Release Tablets whole. Do not chew, crush or split the tablets.

• For the treatment of duodenal ulcers take Rabeprazole Sodium Delayed-Release Tablets after a meal.

• For Helicobacter pylori eradication take Rabeprazole Sodium Delayed-Release Tablets with food.

• For all other indications Rabeprazole Sodium 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.

* pain, swelling or discomfort 

* headaches, dizziness, or weakness 

* unusual bruising (bruises that happen without known cause or that grow in size) 

* nosebleeds 

* bleeding gums 

* bleeding from cuts take a long time to stop 

* menstrual bleeding that is heavier than normal 

* pink or brown urine 

* red or black stools 

* coughing up blood 

* vomiting blood or vomit that looks like coffee grounds 

* Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet).
* You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes.

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

CIA76375P

Rev. 07/2023

2 DOSAGE AND ADMINISTRATION

Table 1 shows the recommended dosage of Rabeprazole Sodium Delayed-Release Tablets in adults and adolescent patients 12 years of age and older. The use of Rabeprazole Sodium Delayed-Release Tablets is not recommended for use in pediatric patients 1 year to less than 12 years of age because the lowest available tablet strength (20 mg) exceeds the recommended dose for these patients. Use another rabeprazole formulation for pediatric patients 1 year to less than 12 years of age.

Table 1: Recommended Dosage and Duration of Rabeprazole Sodium Delayed- Release Tablets in

Adults and Adolescents 12 Years of Age and Older

• For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Rabeprazole Sodium Delayed-Release Tablets 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 Rabeprazole Sodium Delayed-Release Tablets whole. Do not chew, crush, or split tablets.

• For the treatment of duodenal ulcers take Rabeprazole Sodium Delayed-Release Tablets after a meal.

• For Helicobacter pylori eradication take Rabeprazole Sodium Delayed-Release Tablets with food.

• For all other indications Rabeprazole Sodium 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.