Aciphex

(Rabeprazole Sodium)

Check Drug InteractionsCheck known drug interactions.

Aciphex Prescribing Information

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 Healing of Erosive or Ulcerative GERD in Adults
ACIPHEX delayed-release tablets are indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of ACIPHEX may be considered.
).
Maintenance of Healing of Erosive or Ulcerative GERD (
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.
).
Treatment of Symptomatic GERD (
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.
).
Healing of Duodenal Ulcers (
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.
).
Helicobacter pylori
Eradication to Reduce Risk of Duodenal Ulcer Recurrence (
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
]
.
).
Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (
1.6 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults
ACIPHEX delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
).

In adolescent patients 12 years of age and older for:

Short-term Treatment of Symptomatic GERD (
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.
).

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.

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 weeksFor those patients who have not healed after 8 weeks of treatment, an additional 8-week course of ACIPHEX may be considered.

Maintenance of Healing of Erosive or Ulcerative GERD 20 mg once daily Controlled studies do not extend beyond 12 months

Symptomatic GERD in Adults 20 mg once daily Up to 4 weeksIf symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered.

Healing of Duodenal Ulcers 20 mg once daily after the morning meal Up to 4 weeksMost patients heal within 4 weeks; some patients may require additional therapy to achieve healing.

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

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 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 negative¹³C-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 RACThe 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.	10-day OAC
Per ProtocolPatients were included in the analysis if they had H. pylori infection documented at baseline, defined as a positive¹³C-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.	84.3% (N=166)	81.6% (N=179)	2.8 [- 5.2, 10.7]
Intent-to-TreatPatients 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.	77.3% (N=194)	73.3% (N=206)	4.0 [- 4.4, 12.5]
	10-day RAC	10-day OAC
Per Protocol	86.0% (N=171)	81.6% (N=179)	4.4 [- 3.3, 12.1]
Intent-to-Treat	78.1% (N=196)	73.3% (N=206)	4.8 [- 3.6, 13.2]
	3-day RAC	10-day OAC
Per Protocol	29.9% (N=167)	81.6% (N=179)	- 51.6 [- 60.6, - 42.6]
Intent-to-Treat	27.3% (N=187)	73.3% (N=206)	- 46.0 [- 54.8, - 37.2]

The recommended dosage of ACIPHEX delayed-release tablets is 20 mg twice daily with amoxicillin and clarithromycin for 7 days.

]

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

Pediatric Use

: Dosage strength not appropriate for patients less than 12 years (

2 DOSAGE AND ADMINISTRATION

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 weeksFor those patients who have not healed after 8 weeks of treatment, an additional 8-week course of ACIPHEX may be considered.
Maintenance of Healing of Erosive or Ulcerative GERD	20 mg once daily	Controlled studies do not extend beyond 12 months
Symptomatic GERD in Adults	20 mg once daily	Up to 4 weeksIf symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered.
Healing of Duodenal Ulcers	20 mg once daily after the morning meal	Up to 4 weeksMost patients heal within 4 weeks; some patients may require additional therapy to achieve healing.
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

Indication	Recommended Dosage
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

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.

Administration Instructions

Swallow ACIPHEX delayed-release tablets whole. Do not chew, crush, or split tablets.
For the treatment of duodenal ulcers take ACIPHEX delayed-release tablets after a meal.
For
Helicobacter pylori
eradication take ACIPHEX delayed-release tablets with food.
For all other indications ACIPHEX delayed-release tablets can be taken with or without food.
Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and go back to the normal schedule. Do not take two doses at the same time.

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 ACIPHEX delayed-release tablets in this age group is supported by adequate and well controlled studies in adults and a multicenter, randomized, open-label, parallel-group study in 111 adolescent patients 12 to 16 years of age. Patients had a clinical diagnosis of symptomatic GERD, or suspected or endoscopically proven GERD and were randomized to either 10 mg or 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse reaction profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥2% of patients were headache (5%) and nausea (2%). There were no adverse reactions reported in these studies that were not previously observed in adults.

The safety and effectiveness of ACIPHEX delayed-release tablets have not been established in pediatric patients for:

Healing of Erosive or Ulcerative GERD
Maintenance of Healing of Erosive or Ulcerative GERD
Treatment of Symptomatic GERD
Healing of Duodenal Ulcers
Helicobacter pylori
Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

ACIPHEX delayed-release 20 mg tablets are not recommended for use in pediatric patients less than 12 years of age because the tablet strength exceeds the recommended dose for these patients

[see Dosage and Administration (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.

ACIPHEX is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria
[see
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 ACIPHEX and evaluate patients with suspected acute TIN
[see Contraindication (4)]
.
,
6 ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere in labeling:
Acute Tubulointerstitial Nephritis
[see Warnings and Precautions (5.3)]
Clostridium difficile-
Associated Diarrhea
[see Warnings and Precautions (5.4)]
Bone Fracture
[see Warnings and Precautions (5.5)]
Cutaneous and Systemic Lupus Erythematosus
[see Warnings and Precautions (5.7)]
Cyanocobalamin (Vitamin B-12) Deficiency
[see Warnings and Precautions (5.8)]
Hypomagnesemia and Mineral Metabolism
[see Warnings and Precautions (5.9)]
Fundic Gland Polyps
[see Warnings and Precautions (5.11)]
Most common adverse reactions in adults (>2%) are pain, pharyngitis, flatulence, infection, and constipation .
Most common adverse reactions in adolescents (≥2%) are headache, diarrhea, nausea, vomiting, and abdominal pain .

To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC at 1-844-944-0912 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
6.1 Clinical Studies Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults
The data described below reflect exposure to ACIPHEX delayed-release tablets in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in adult patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male: 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian, and 5% other. Most patients received either 10 mg, 20 mg or 40 mg per day of ACIPHEX delayed-release tablets.
An analysis of adverse reactions appearing in ≥2% of patients treated with ACIPHEX delayed-release tablets (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).
Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to ACIPHEX delayed-release tablets for 6 months and at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of ACIPHEX delayed-release tablets, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies.
Less common adverse reactions seen in controlled clinical trials (<2% of patients treated with ACIPHEX delayed-release tablets and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.
Combination Treatment with Amoxicillin and Clarithromycin:
In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.
No clinically significant laboratory abnormalities particular to the drug combinations were observed.
For more information on adverse reactions or laboratory changes with amoxicillin or clarithromycin, refer to their respective prescribing information,
Adverse Reactions
section.
Pediatrics
In a multicenter, open-label study of adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to ACIPHEX delayed-release tablets that occurred in ≥2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in this study that were not previously observed in adults.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of rabeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Blood and Lymphatic System Disorders:
agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia
Ear and Labyrinth Disorders:
vertigo
Eye Disorders:
blurred vision
Gastrointestinal Disorders:
fundic gland polyps
General Disorders and Administration Site Conditions:
sudden death
Hepatobiliary Disorders:
jaundice
Immune System Disorders:
anaphylaxis, angioedema, systemic lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), DRESS, AGEP
Infections and Infestations: Clostridium difficile
-associated diarrhea
Investigations:
Increases in prothrombin time/INR (in patients treated with concomitant warfarin), TSH elevations
Metabolism and Nutrition Disorders:
hyperammonemia, hypomagnesemia, hypocalcemia, hypokalemia
[Warnings and Precautions 5.8]
, hyponatremia
Musculoskeletal System Disorders:
bone fracture, rhabdomyolysis
Nervous System Disorders:
coma
Psychiatric Disorders:
delirium, disorientation
Renal and Genitourinary Disorders:
interstitial nephritis, erectile dysfunction
Respiratory, Thoracic and Mediastinal Disorders:
interstitial pneumonia
Skin and Subcutaneous Tissue Disorders:
severe dermatologic reactions including bullous and other drug eruptions of the skin, cutaneous lupus erythematosus, erythema multiforme
]
.

PPIs, including ACIPHEX, are contraindicated with rilpivirine-containing products

[see

7 DRUG INTERACTIONS

Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics 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 and Interactions with Diagnostics
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 (5.9)].
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., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving ACIPHEX delayed-release tablets 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.
Tacrolimus
Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors .
Intervention:	Temporarily stop ACIPHEX delayed-release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop treatment with ACIPHEX delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline.
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.

See full prescribing information for a list of clinically important drug interactions .

]

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with ACIPHEX delayed-release tablets, refer to the
Contraindications
section of their package inserts.

Gastric Malignancy
: In adults, symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing (
5.1 Presence of Gastric Malignancy
In adults, symptomatic response to therapy with ACIPHEX does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI.
).

Use with Warfarin

: Monitor for increases in INR and prothrombin time (

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 ACIPHEX delayed-release tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time

[see Drug Interactions (7)]

7 DRUG INTERACTIONS

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 and Interactions with Diagnostics
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 (5.9)].
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., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving ACIPHEX delayed-release tablets 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.
Tacrolimus
Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors .
Intervention:	Temporarily stop ACIPHEX delayed-release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop treatment with ACIPHEX delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline.
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.

See full prescribing information for a list of clinically important drug interactions .

Acute Tubulointerstitial Nephritis
: Discontinue treatment and evaluate patients (
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 ACIPHEX and evaluate patients with suspected acute TIN
[see Contraindication (4)]
.
).
Clostridium difficile
-Associated Diarrhea
: PPI therapy may be associated with increased risk of (
5.4
Clostridium difficile
-Associated Diarrhea
Published observational studies suggest that PPI therapy like ACIPHEX may be associated with an increased risk of
Clostridium difficile
-associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve
[see Adverse Reactions (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.
).
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 (
5.5 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)]
.
).
Severe Cutaneous Adverse Reactions
:
Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation (
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 ACIPHEX at first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
).
Cutaneous and Systemic Lupus Erythematosus
: Mostly cutaneous, new onset or exacerbation of existing disease; discontinue ACIPHEX and refer to specialist for 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 ACIPHEX, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
).
Cyanocobalamin (Vitamin B-12) Deficiency
: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin (5.8).
Hypomagnesemia and Mineral Metabolism
: Reported rarely with prolonged treatment with PPIs (
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), health care 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 ACIPHEX 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.
).

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 (

5.10 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)]

7 DRUG INTERACTIONS

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 and Interactions with Diagnostics
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 (5.9)].
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., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving ACIPHEX delayed-release tablets 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.
Tacrolimus
Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors .
Intervention:	Temporarily stop ACIPHEX delayed-release tablets treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop treatment with ACIPHEX delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline.
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.

See full prescribing information for a list of clinically important drug interactions .

Fundic Gland Polyps
: Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy (
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.
).

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