Aciphex

Name: Aciphex

Aciphex Dosage

Aciphex comes in 20-milligram (mg) delayed-release tablets, which should be swallowed whole.

To treat GERD, an adult and adolescent should take one tablet daily. To heal a duodenal ulcer, an adult should take one tablet daily 30 minutes before breakfast.

For a hypersecretory condition, such as Zollinger-Ellison syndrome, the dose for an adult generally starts with 60 mg of Aciphex daily, though the dosage can be adjusted as necessary.

Treating an infection of H. pylori requires 20 mg of Aciphex, 1000 mg of amoxicillin, and 500 mg of clarithromycin, all of which should be taken twice daily with breakfast and dinner for 7 days.

Aciphex also comes in the form of Aciphex Sprinkle - 5 mg and 10 mg delayed-release capsules - for children.

After opening the capsule, you sprinkle the drug contents onto a spoonful of soft food, such as applesauce, or a liquid. The whole dose should be taken within 15 minutes of being sprinkled, 30 minutes before a meal.

Children who weigh less than 33 pounds (15 kilograms) should take 5 mg once daily, and children who weigh more than that should take 10 mg once daily.

Aciphex Overdose

There are no reports of large Aciphex overdoses, and a moderate overdose causes no symptoms.

However, research in rodents shows that large doses of Aciphex cause decreased activity, difficulty breathing, and convulsions.

In dog studies, large doses caused watery diarrhea, tremors, convulsions, and coma.

Contact a poison control center or emergency room if you suspect you've taken too much Aciphex. You can get in touch with a poison control center at (800) 222-1222.

Missed Dose of Aciphex

Take your missed dose as soon as possible.

If it's almost time for your next dose, skip the missed dose and continue on your regular dosing schedule.

Don't double up on doses to make up for a missed one.

Why is this medication prescribed?

Rabeprazole is used to treat gastroesophageal reflux disease (GERD), a condition in which backward flow of acid from the stomach causes heartburn and possible injury of the esophagus (the tube that connects the throat and stomach). Rabeprazole is used to treat the symptoms of GERD, allow the esophagus to heal, and prevent further damage to the esophagus. Rabeprazole is also used to treat conditions in which the stomach produces too much acid, such as Zollinger-Ellison syndrome. Rabeprazole is used to treat ulcers (sores in the lining of the stomach or intestine) and is used in combination with other medications to eliminate H. pylori, a bacteria that causes ulcers. Rabeprazole is in a class of medications called proton-pump inhibitors. It works by decreasing the amount of acid made in the stomach.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

What side effects can this medication cause?

Rabeprazole may cause side effects. Tell your doctor if these symptoms are severe or do not go away:

  • headache
  • nausea
  • vomiting
  • constipation
  • gas
  • sore throat

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately, or get emergency medical help:

  • blistering or peeling skin
  • rash
  • hives
  • swelling of the eyes, face, mouth, lips, tongue, or throat
  • difficulty breathing or swallowing
  • irregular, fast, or pounding heartbeat
  • excessive tiredness
  • dizziness
  • lightheadedness
  • muscle spasms
  • uncontrollable shaking of a part of the body
  • seizures
  • severe diarrhea with watery stools
  • stomach pain
  • fever

Rabeprazole may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.

People who take proton pump inhibitors such as rabeprazole may be more likely to fracture their wrists, hips, or spine than people who do not take one of these medications. The risk is highest in people who take high doses of one of these medications or take them for one year or longer. Talk to your doctor about the risk of taking rabeprazole.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

What should I discuss with my healthcare provider before taking rabeprazole?

Heartburn is often confused with the first symptoms of a heart attack. Seek emergency medical attention if you have chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, and a general ill feeling.

You should not use this medicine if you are allergic to rabeprazole or:

  • if you also take any medicine that contains rilpivirine, such as Edurant or Complera; or

  • if you also allergic to medicines like rabeprazole, such as esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec, Zegerid), or pantoprazole (Protonix).

To make sure rabeprazole is safe for you, tell your doctor if you have:

  • liver disease;

  • osteoporosis;

  • low bone mineral density (osteopenia); or

  • low levels of magnesium in your blood.

Taking a proton pump inhibitor such as rabeprazole may increase your risk of bone fracture in the hip, wrist, or spine. This effect has occurred mostly in people who have taken the medicine long term or at high doses, and in those who are age 50 and older. It is not clear whether rabeprazole is the actual cause of an increased risk of fracture.

This medicine is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether rabeprazole passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

What other drugs will affect rabeprazole?

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • methotrexate (Otrexup, Rasuvo,Trexall); or

  • warfarin (Coumadin, Jantoven).

This list is not complete. Other drugs may interact with rabeprazole, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Introduction

Acid- or proton-pump inhibitor; gastric antisecretory agent.1 2 3 4 5 6

Uses for AcipHex

Gastroesophageal Reflux (GERD)

Short-term treatment of symptomatic GERD (e.g., heartburn) in patients without erosive esophagitis.1

Short-term treatment of erosive esophagitis in patients with GERD.1 2 3 15 18

Maintain healing and decrease recurrence of erosive esophagitis.1 2 3

Duodenal Ulcer

Short-term treatment of active duodenal ulcer.1 2 3 17

Treatment of Helicobacter pylori infection and duodenal ulcer disease.1 Used in conjunction with amoxicillin and clarithromycin (triple therapy).1

Pathologic GI Hypersecretory Conditions

Long-term treatment of pathologic GI hypersecretory conditions (e.g., Zollinger-Ellison syndrome).1 3

Crohn’s Disease-associated Ulcers

Some evidence for use of proton-pump inhibitors (e.g., omeprazole) for gastric acid suppressive therapy as an adjunct in the management of upper GI Crohn’s disease†, including esophageal†, gastroduodenal†, and jejunoileal† disease.27 28 29 31 32 33

Indications and usage

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 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.

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.

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

Table 3: Gastric Acid Parameters: Aciphex Delayed-Release Tablets versus Placebo After 7 Days of Once Daily Dosing
Parameter Aciphex delayed-release tablets
(20 mg once daily)
Placebo
Basal Acid Output (mmol/hr) 0.4* 2.8
Stimulated Acid Output (mmol/hr) 0.6* 13.3
% Time Gastric pH>3 65* 10

*(p<0.01 versus placebo)

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

Table 4: AUC Acidity (Mmol•Hr/L): Aciphex Delayed-Release Tablets versus Placebo on Day 7 of Once Daily Dosing (Mean±SD)
Aciphex delayed-release tablets      
Placebo
(N=24)
AUC interval
(hrs)
10 mg
(N=24)
20 mg
(N=24)
40 mg
(N=24)
08:00 – 13:00 19.6±21.5* 12.9±23* 7.6±14.7* 91.1±39.7
13:00 – 19:00 5.6±9.7* 8.3±29.8* 1.3±5.2* 95.5±48.7
19:00 – 22:00 0.1±0.1* 0.1±0.06* 0.0±0.02* 11.9±12.5
22:00 – 08:00 129.2±84* 109.6±67.2* 76.9±58.4* 479.9±165
AUC 0-24
hours
155.5±90.6* 130.9±81* 85.8±64.3* 678.5±216

*(p<0.001 versus placebo)

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

Table 5: Gastric Acid Parameters Aciphex Delayed-Release Tablets Once Daily Dosing versus Placebo on Day 1 and Day 8
Parameter Aciphex delayed-release tablets 20 mg once daily Placebo
Day 1 Day 8 Day 1 Day 8
Mean AUC0-24 Acidity 340.8* 176.9* 925.5 862.4
Median trough pH (23-hr)a 3.77 3.51 1.27 1.38
% Time Gastric pH greater than 3b 54.6* 68.7* 19.1 21.7
% Time Gastric pH greater than 4b 44.1* 60.3* 7.6 11.0

a No inferential statistics conducted for this parameter.
b Gastric pH was measured every hour over a 24-hour period.
* (p<0.001 versus placebo)

Effects on Esophageal Acid Exposure

In patients with GERD and moderate to severe esophageal acid exposure, a dose of 20 mg and 40 mg per day of Aciphex delayed-release tablets decreased 24-hour esophageal acid exposure.  After seven days of treatment, the percentage of time that the esophageal pH was less than 4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively.  Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH greater than 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving Aciphex 20 mg and in 100% of subjects receiving Aciphex 40 mg.  With Aciphex 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.

Effects on Serum Gastrin

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

In a group of subjects treated with 20 mg Aciphex delayed-release tablets for 4 weeks a doubling of mean serum gastrin concentrations was observed.  Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal.

Effects on Enterochromaffin-like (ECL) Cells

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

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

Endocrine Effects

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

Other Effects

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

12.3 Pharmacokinetics

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

Absorption

Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%.  When Aciphex delayed-release tablets are administered with a high fat meal, Tmax is variable; which concomitant food intake may delay the absorption up to 4 hours or longer.  However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered.  Thus Aciphex delayed-release tablets may be taken without regard to timing of meals.

Distribution

Rabeprazole is 96.3% bound to human plasma proteins.

Elimination

Metabolism:  Rabeprazole is extensively metabolized.  A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound.  Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver.  The thioether and sulphone are the primary metabolites measured in human plasma.  These metabolites were not observed to have significant antisecretory activity.  In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3 to 5% of Caucasians and 17 to 20% of Asians).  Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.

Excretion:  Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites.  The remainder of the dose was recovered in the feces.  Total recovery of radioactivity was 99.8%.  No unchanged rabeprazole was recovered in the urine or feces.

Specific Populations

Age: Geriatric Population:  In 20 healthy elderly subjects administered 20 mg Aciphex delayed-release tablets once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration [see Use in Specific Population (8.5)].

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

Sex and Race/Ethnicity:  In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects.  In studies that used different formulations of rabeprazole, AUC0-∞ values for healthy Japanese men were approximately 50 to 60% greater than values derived from pooled data from healthy men in the United States.

Renal Impairment:  In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg dose of Aciphex delayed-release tablets when compared to 10 healthy subjects.

Hepatic Impairment:  In a single dose study of 10 patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a single 20 mg dose of Aciphex delayed-release tablets, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg Aciphex delayed-release tablets once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects.  These increases were not statistically significant.

No information exists on rabeprazole disposition in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)]. 

Drug Interaction Studies

Combined Administration with Antimicrobials:  Sixteen healthy subjects genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg Aciphex delayed-release tablets, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study.  Each of the four regimens was administered twice daily for 6 days.  The AUC and Cmax for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration.  However, the rabeprazole AUC and Cmax increased by 11% and 34%, respectively, following combined administration.  The AUC and Cmax for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively.  This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns.

Effects of Other Drugs on Rabeprazole

Antacids: Co-administration of Aciphex delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

Effects of Rabeprazole on Other Drugs

Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as theophylline (CYP1A2) given as single oral doses, diazepam (CYP2C9 and CYP3A4) as a single intravenous dose, and phenytoin (CYP2C9 and CYP2C19) given as a single intravenous dose (with supplemental oral dosing).  Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.

Clopidogrel:  Clopidogrel is metabolized to its active metabolite in part by CYP2C19.  A study of healthy subjects including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with 20 mg Aciphex delayed-release tablets (n=36), for 7 days was conducted.  The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when Aciphex delayed-release tablets were coadministered compared to administration of clopidogrel with placebo [see Drug Interactions (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 Aciphex 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 Outcomesa for a Three Drug Regimen (Aciphex Delayed-Release Tablets 20 mg Twice Daily, Amoxicillin 1000 mg Twice Daily, and Clarithromycin 500 mg Twice Daily for 7 or 10 Days)
Days of RAC Therapy Clarithromycin Pretreatment Results Total Number H. pylori Negative (Eradicated) H. pylori Positive (Persistent)
Post-Treatment Susceptibility Results
S b I b R b No MIC
7 Susceptible b 129 103 2 0 1 23
7 Intermediate b 0 0 0 0 0 0
7 Resistant b 16 5 2 1 4 4
10 Susceptible b 133 111 3 1 2 16
10 Intermediate b 0 0 0 0 0 0
10 Resistant b 9 1 0 0 5 3

a Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results.
b Susceptible (S) MIC ≤0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥1 mcg/mL

Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates.  Therefore, clarithromycin susceptibility testing should be done when possible.  If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes:  In the U.S. multicenter study, greater than 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤0.25 mcg/mL) to amoxicillin at baseline.  The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated.  In the 7- and 10-day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori.  No patients developed amoxicillin-resistant H. pylori during therapy.

12.5 Pharmacogenomics

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

References

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved StandardTenth Edition.  CLSI Document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania, 19087, USA 2015.

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)].
  • 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 (5.6)].
  • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7)].
  • Hypomagnesemia [see Warnings and Precautions (5.8)]. 

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, 5.9)].

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.

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MEDICATION GUIDE
Aciphex® (a-se-feks)
(rabeprazole sodium)
delayed-release tablets
Read the Medication Guide that comes with Aciphex before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.
What is the most important information I should know about Aciphex?
Aciphex may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.
Aciphex can cause serious side effects, including:
  • A type of kidney problem (acute interstitial nephritis).  Some people who take proton pump inhibitor (PPI) medicines, including Aciphex, may develop a kidney problem called acute interstitial nephritis that can happen at any time during treatment with Aciphex. Call your doctor if you have a decrease in the amount that you urinate or if you have blood in your urine.
  • Diarrhea. Aciphex may increase your risk of getting severe diarrhea. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines.
    Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away. 
  • Bone fractures.  People who take multiple daily doses of PPI medicines for a long period of time (1 year or longer) may have an increased risk of fractures of the hip, wrist, or spine. You should take Aciphex exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed.
  • Certain types of lupus erythematosus.  Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including Aciphex, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun.
Talk to your doctor about your risk of these serious side effects if you take Aciphex.  
Aciphex can have other serious side effects. See “What are the possible side effects of Aciphex?”
What is Aciphex?
Aciphex is a prescription medicine called a proton pump inhibitor (PPI).
Aciphex reduces the amount of acid in your stomach.
Aciphex is used in adults:
  • for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) and to relieve symptoms, such as heartburn pain. If needed, your doctor may decide to prescribe another 8 weeks of Aciphex.
  • to maintain the healing of the esophagus and relief of symptoms related to EE. It is not known if Aciphex is safe and effective if used longer than 12 months (1 year).
  • for up to 4 weeks to treat daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD).
    GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.
  • for up to 4 weeks for the healing and relief of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
  • for 7 days with certain antibiotic medicines to treat an infection caused by bacteria called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back.
  • for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison syndrome.
Aciphex is used in adolescents 12 years of age and older to treat symptoms of Gastroesophageal Reflux Disease (GERD) for up to 8 weeks.
It is not known if Aciphex is safe and effective in children to:
  • heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE)
  • maintain the healing of the esophagus and relief of symptoms related to EE
  • treat symptoms that happen with Gastroesophageal Reflux Disease (GERD)
  • heal duodenal ulcers
  • treat an infection caused by bacteria called H. pylori to reduce the risk of duodenal ulcers from coming back
  • treat conditions where your stomach makes too much acid, including Zollinger-Ellison Syndrome.
Aciphex delayed-release tablets should not be used in children under 12 years of age.
Who should not take Aciphex?
Do not take Aciphex if you:
  • are allergic to rabeprazole or any of the other ingredients in Aciphex. See the end of this Medication Guide for a complete list of ingredients in Aciphex.
  • are allergic to any other proton pump inhibitor (PPI) medicine
  • are taking a medicine that contains rilpivirine (Edurant, Complera) used to treat HIV-1 (Human Immunodeficiency Virus)
What should I tell my doctor before taking Aciphex?
Before you take Aciphex tell your doctor if you:
  • have been told that you have low magnesium levels in your blood
  • have liver problems
  • have any allergies
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if Aciphex can harm your unborn baby. Talk to your doctor about the possible risks to an unborn baby if Aciphex is taken during pregnancy.
  • are breastfeeding or plan to breastfeed. It is not known if Aciphex passes into your breast milk or if it will affect your baby or your breast milk. Talk to your doctor about the best way to feed your baby if you take Aciphex.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Aciphex may affect how other medicines work, and other medicines may affect how Aciphex works.  Especially tell your doctor if you take an antibiotic that contains clarithromycin or amoxicillin or if you take warfarin (COUMADIN, JANTOVEN) or methotrexate (Otrexup, Rasuvo, Trexall).
Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take Aciphex?
  • Take Aciphex exactly as prescribed. Your doctor will prescribe the dose that is right for you and your medical condition. Do not change your dose or stop taking Aciphex unless you talk to your doctor. Take Aciphex for as long as it is prescribed even if you feel better.
  • Aciphex is usually taken 1 time each day. Your doctor will tell you the time of day to take Aciphex, based on your medical condition.
  • Aciphex can be taken with or without food. Your doctor will tell you whether to take this medicine with or without food based on your medical condition.
  • Swallow each Aciphex tablet whole. Do not chew, crush, or split Aciphex tablets. Tell your doctor if you cannot swallow tablets whole.
  • If you miss a dose of Aciphex, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
  • If you take too much Aciphex, call your doctor or your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.
  • Your doctor may prescribe antibiotic medicines with Aciphex to help treat a stomach infection and heal stomach (duodenal) ulcers that are caused by bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it. 
What are the possible side effects of Aciphex?
Aciphex may cause serious side effects, including:
  • See “What is the most important information I should know about Aciphex?”
  • Interaction with warfarin. Taking warfarin with a PPI medicine may lead to an increased risk of bleeding and death. If you take warfarin, your doctor may check your blood to see if you have an increased risk of bleeding.  If you take warfarin during treatment with Aciphex, tell your doctor right away if you have any signs or symptoms of bleeding, including:
    ° unexpected bleeding or bleeding that lasts a long time, such as:
     ▪ nosebleeds that happen often
     ▪ unusual bleeding from the gums
     ▪ menstrual bleeding that is heavier than normal or unusual vaginal bleeding
     ▪ bleeding that is severe or that you cannot control
    ° red, pink or brown urine
    ° bright red or black stools (looks like tar)
    ° coughing up blood or blood clots
    ° vomiting blood or your vomit looks like “coffee grounds”
    ° headaches
    ° feel dizzy or weak
  • Vitamin B-12 deficiency.  Aciphex reduces the amount of acid in your stomach. Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor about the possibility of vitamin B-12 deficiency if you have been on Aciphex for a long time (more than 3 years).
  • Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a PPI medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.
Tell your doctor right away and get medical care if you have any of these symptoms:
  • seizures
  • dizziness
  • abnormal or fast heart beat
  • jitteriness
  • jerking movements or shaking (tremors)
  • muscle weakness
  • spasms of the hands and feet
  • cramps or muscle aches
  • spasm of the voice box
Your doctor may check the level of magnesium in your body before you start taking Aciphex, during treatment, or if you will be taking Aciphex for a long period of time.
The most common side effects of Aciphex in adults include:
  • pain
  • sore throat
  • gas
  • infection
  • constipation
The most common side effects of Aciphex in adolescents 12 years of age and older include:
  • headache
  • diarrhea
  • nausea
  • vomiting
  • stomach-area (abdomen) pain
Other side effects:
Serious allergic reactions. Tell your doctor if you get any of the following symptoms with Aciphex:
  • rash
  • face swelling
  • throat tightness
  • difficulty breathing
Your doctor may stop Aciphex if these symptoms happen.
These are not all of the possible side effects of Aciphex.  Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Aciphex?
Store Aciphex Tablets in a dry place at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
Keep Aciphex and all medicines out of the reach of children.
General Information about Aciphex
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Aciphex for a condition for which it was not prescribed. Do not give Aciphex to other people, even if they have the same symptoms that you have. It may harm them.
You can ask your doctor or pharmacist for information about Aciphex that is written for health professionals.
What are the ingredients in Aciphex?
Active ingredient: rabeprazole sodium
Inactive ingredients: carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating.  Iron oxide red is the ink pigment.
Distributed by Eisai Inc., Woodcliff Lake, NJ 07677
All brand names are the trademarks of their respective owners.
For more information, go to http://www.Aciphex.com/ or call 1-888-4-Aciphex. 

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: October 2016

PRINCIPAL DISPLAY PANEL

NDC 62856-243-30
Aciphex
rabeprazole Sodium
delayed- release
tablets
20 mg
30 tablets
Rx Only

Aciphex 
rabeprazole sodium tablet, delayed release
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:62856-243
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
RABEPRAZOLE SODIUM (RABEPRAZOLE) RABEPRAZOLE SODIUM 20 mg
Inactive Ingredients
Ingredient Name Strength
CARNAUBA WAX  
CROSPOVIDONE  
DIACETYLATED MONOGLYCERIDES  
ETHYLCELLULOSES  
HYDROXYPROPYL CELLULOSE (TYPE H)  
HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST)  
MAGNESIUM STEARATE  
MANNITOL  
PROPYLENE GLYCOL  
SODIUM HYDROXIDE  
SODIUM STEARYL FUMARATE  
TALC  
TITANIUM DIOXIDE  
FERRIC OXIDE YELLOW  
FERRIC OXIDE RED  
Product Characteristics
Color YELLOW (yellow) Score no score
Shape ROUND (ROUND) Size 8mm
Flavor Imprint Code Aciphex;20
Contains     
Packaging
# Item Code Package Description
1 NDC:62856-243-41 100 BLISTER PACK in 1 CARTON
1 1 TABLET, DELAYED RELEASE in 1 BLISTER PACK
2 NDC:62856-243-30 30 TABLET, DELAYED RELEASE in 1 BOTTLE
3 NDC:62856-243-90 90 TABLET, DELAYED RELEASE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020973 08/19/1999
Labeler - Eisai Inc. (831600833)
Revised: 10/2016   Eisai Inc.

Manufacturer

  • Bryant Ranch Prepack

  • Cardinal Health, Inc.

  • DispenseXpress, Inc.

  • Dispensing Solutions, Inc.

  • Eisai, Inc

  • Lake Erie Medical & Surgical Supplies DBA Quality Care Products LLC

  • Lake Erie Medical & Surgical Supply DBA Quality Care Produtcs LLC

  • Nuline Pharmaceuticals, LLC

  • Quality Care Products, LLC

  • Stat Rx Usa Llc

Aciphex and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Aciphex is excreted in human breast milk or if it can harm your nursing baby. Since many drugs can pass into breastmilk, and because of the possibility for serious reactions to infants from Aciphex, a decision should be made to stop nursing or the drug. The importance of the drug to the mother should be considered.

What is AcipHex?

AcipHex (rabeprazole) is a proton pump inhibitor that decreases the amount of acid produced in the stomach.

AcipHex is used short-term to treat symptoms of gastroesophageal reflux disease (GERD) in adults and children who are at least 1 year old.

AcipHex is used only in adults to treat conditions involving excessive stomach acid, such as Zollinger-Ellison syndrome. Rabeprazole is also used in adults to promote healing of duodenal ulcers or erosive esophagitis (damage to your esophagus caused by stomach acid).

AcipHex may also be given with an antibiotic to prevent duodenal ulcer caused by infection with Helicobacter pylori (H. pylori).

This medicine is not for immediate relief of heartburn symptoms.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Rabeprazole Pregnancy Warnings

This drug should be used during pregnancy only if the benefit outweighs the risk. -Some experts state that use is contraindicated. AU TGA pregnancy category: B1 US FDA pregnancy category: Not assigned. Risk summary: No data available on use of this drug in pregnant women to inform a drug-related risk

Animal studies have failed to reveal evidence of teratogenicity or fetal harm, though animal models given this drug at high doses in late gestation through lactation had changes in bone morphology and decreased pup weight gain. There are no controlled data in human pregnancy. AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Rabeprazole Breastfeeding Warnings

In animal models, this drug and its metabolites are excreted into breastmilk. When administered to animal models via IV, milk levels of this drug were higher than blood levels, and pups that were exposed had decreased weight gain.

Use is not recommended and a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. -Some experts state that use is contraindicated. Excreted into human milk: Unknown Excreted into animal milk: Yes Comment: The effects in the nursing infant are unknown.

Rabeprazole Levels and Effects while Breastfeeding

Summary of Use during Lactation

Because no information is available on the use of rabeprazole during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Cimetidine, Famotidine, Nizatidine, Omeprazole, Pantoprazole, Ranitidine, Sucralfate

References

Administrative Information

LactMed Record Number

410

Last Revision Date

20130907

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.

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