RABEprazole sodium 20 MG Delayed Release Oral Tablet
Generic Name: RABEPRAZOLE SODIUM
Brand Name: AcipHex
- Substance Name(s):
- RABEPRAZOLE SODIUM
DRUG INTERACTIONS
7 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 (4) ].
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 (5.2) ].
Intervention: Monitor INR and prothrombin time.
Dose adjustment of warfarin may be needed to maintain target INR range.
See prescribing information for warfarin.
Methotrexate Clinical Impact: Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities.
No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.8) ].
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 (12.3) ] .
Intervention: Monitor digoxin concentrations.
Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations.
See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., ir on salts, erlotinib, dasatinib, nilotinib, mycophenol ate 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 information for clarithromycin.
See Drug Interactions in prescribing information for amoxicillin.
See full prescribing information for a list of clinically important drug interactions (7).
OVERDOSAGE
10 Seven reports of accidental overdosage with rabeprazole have been received.
The maximum reported overdose was 80 mg.
There were no clinical signs or symptoms associated with any reported overdose.
Patients with Zollinger-Ellison syndrome have been treated with up to 120 mg rabeprazole once daily.
No specific antidote for rabeprazole is known.
Rabeprazole is extensively protein bound and is not readily dialyzable.
In the event of overdosage, treatment should be symptomatic and supportive.
If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.
DESCRIPTION
11 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-(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: Figure 1 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.
ACIPHEX is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium.
CLINICAL STUDIES
14 Mean Daytime Heartburn Scores RAB-USA-2 Mean Nighttime Heartburn Scores RAB-USA-2 Mean Daytime Heartburn Scores RAB-USA-3 Mean Nighttime Heartburn Scores RAB-USA-3 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 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.
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 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 57/6 (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<p<0.05 versus placebo 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX delayed-release tablets also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).
The recommended dosage of ACIPHEX delayed-release tablets is 20 mg once daily for 4 weeks.
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 ACIPHEX delayed-release tablets once daily versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks.
ACIPHEX was significantly superior to placebo in producing healing of duodenal ulcers.
The percentages of patients with endoscopic healing are presented below: Table 11: Healing of Duodenal Ulcers Percentage of Patients Healed Week ACIPHEX delayed-release tablets Placebo N=33 20 mg once daily N=34 40 mg once daily N=33 2 44% 42% 21% 4 79%* 91%* 39% * p≤0.001 versus placebo At Weeks 2 and 4, significantly more patients in the ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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, ACIPHEX was comparable to omeprazole in producing healing of duodenal ulcers.
The percentages of patients with endoscopic healing at two and four weeks are presented below: Table 12: Healing of Duodenal Ulcers Percentage of Patients Healed Week ACIPHEX delayed-release tablets 20 mg once daily N=102 Omeprazole 20 mg once daily N=103 95% Confidence Interval for the Treatment Difference (ACIPHEX – Omeprazole) 2 69% 61% (–6%, 22%) 4 98% 93% (–3%, 15%) ACIPHEX and omeprazole were comparable in providing complete resolution of symptoms.
The recommended dosage of ACIPHEX delayed-release tablets is 20 mg once daily for 4 weeks.
14.5 Helicobacter pylori Eradication in Patien ts with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease in Adults The U.S.
multicenter study was a double-blind, parallel-group comparison of ACIPHEX 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 Pylori Eradication at ≥6 Weeks After the End of Treatment Treatment Group Percent (%) of Patients Cured (Number of Patients) Difference (RAC – OAC) [95% Confidence Interval] 7-day RAC* 10-day OAC Per Protocola 84.3% (N=166) 81.6% (N=179) 2.8 [- 5.2, 10.7] Intent-to-Treatb 77.3% (N=194) 73.3% (N=206) 4.0 [- 4.4, 12.5] 10-day RAC* 10-day OAC Per Protocola 86.0% (N=171) 81.6% (N=179) 4.4 [- 3.3, 12.1] Intent-to-Treatb 78.1% (N=196) 73.3% (N=206) 4.8 [- 3.6, 13.2] 3-day RAC 10-day OAC Per Protocola 29.9% (N=167) 81.6% (N=179) – 51.6 [- 60.6, – 42.6] Intent-to-Treatb 27.3% (N=187) 73.3% (N=206) – 46.0 [- 54.8, – 37.2] a Patients were included in the analysis if they had H.
pylori infection documented at baseline, defined as a positive 13C-UBT plus rapid urease test or culture and were not protocol violators.
Patients who dropped out of the study due to an adverse event related to the study drug were included in the evaluable analysis as failures of therapy.
b Patients were included in the analysis if they had documented H.
pylori infection at baseline as defined above and took at least one dose of study medication.
All dropouts were included as failures of therapy.
* The 95% confidence intervals for the difference in eradication rates for 7-day RAC minus 10-day RAC are (- 9.3, 6.0) in the PP population and (-9.0, 7.5) in the ITT population.
The recommended dosage of ACIPHEX 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 ACIPHEX delayed-release tablets at doses from 20 to 120 mg for up to 12 months.
ACIPHEX produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present.
ACIPHEX also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients.
The high doses of ACIPHEX used to treat this small cohort of patients with gastric hypersecretion were well tolerated.
The recommended starting dosage of ACIPHEX delayed-release tablets is 60 mg once daily.
HOW SUPPLIED
Product: 68151-3834 NDC: 68151-3834-3 1 TABLET, DELAYED RELEASE in a PACKAGE
RECENT MAJOR CHANGES
Contraindications (4) 04/2016
GERIATRIC USE
8.5 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.
DOSAGE FORMS AND STRENGTHS
3 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.
Delayed-Release Tablets: 20 mg (3).
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 ACIPHEX 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 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 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.
1.2 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.
1.3 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.
1.4 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.
1.5 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 (12.2) and the full prescribing information for clarithromycin].
1.6 Treatment of Pathological Hypersecretory Conditio ns, 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.
1.7 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.
PEDIATRIC USE
8.4 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 ACIPEX 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 (2) ].
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.
PREGNANCY
8.1 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.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Gastric Malignancy: Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy (5.1).
Use with Warfarin: Monitor for increases in INR and prothombin time (5.2, 7).
Acute Interstitial Nephritis: Observed in patients taking PPIs (5.3).
Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin (5.4).
Clostridium difficile Associated Diarrhea: PPI therapy may be associated with increased risk of (5.5).
Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (5.6).
Hypomagnesemia: Reported rarely with prolonged treatment with PPIs (5.7).
Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity.
With high dose methotrexate administration, consider a temporary withdrawal of ACIPHEX delayed-release tablets (5.8, 7).
5.1 Presence of G astric M alignancy Symptomatic response to therapy with ACIPHEX does not preclude the presence of gastric malignancy.
Patients with healed GERD were treated for up to 40 months with ACIPHEX delayed-release tablets and monitored with serial gastric biopsies.
Patients without H.
pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa.
Patients with H.
pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum.
Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable.
Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable.
At baseline 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum.
At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum.
Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.
5.2 Interaction with W arfarin 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 (7) ].
5.3 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 (4) ] .
5.4 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.
5.
5 Clostridium difficile A ssociated D iarrhea 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 (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 ACIPHEX, refer to Warnings and Precautions sections of the corresponding prescribing information.
5.
6 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.
7 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 (6.2) ].
5.
8 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) ].
INFORMATION FOR PATIENTS
17 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 (4) ].
Acute Interstitial Nephritis [see Warnings and Precautions (5.3) ].
Cyanocobalamin (vitamin B-12) Deficiency [see Warnings and Precautions (5.4) ].
Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.5) ].
Bone Fracture [see Warnings and Precautions (5.6) ].
Hypomagnesemia [see Warnings and Precautions (5.7) ].
Drug Interactions Advise patients to report to their healthcare provider if they are taking warfarin or high-dose methotrexate [see Warnings and Precautions ( 5.2 , 5.8 )].
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.
Distributed by Eisai Inc., Woodcliff Lake, NJ 07677 All brand names are the trademarks of their respective owners.
DOSAGE AND ADMINISTRATION
2 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** Healing of Duodenal Ulcers 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 (14.5) ] 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 Instruction s 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.
Indication Recommended Dosage (2) Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) 20 mg once daily for 4 to 8 weeks Maintenance of Healing of Erosive or Ulcerative GERD *studied for 12 months 20 mg once daily* Symptomatic GERD in Adults 20 mg once daily for 4 weeks Healing of Duodenal Ulcers 20 mg once daily after morning meal for up to 4 weeks Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Three Drug Regimen: ACIPHEX 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg All three medications should be taken twice daily with morning and evening meals for 7 days Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome Starting dose 60 mg once daily then adjust to patient needs Symptomatic GERD in Adolescents 12 Years of Age and Older 20 mg once daily for up to 8 weeks Administration Instructions ( 2 ): 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.