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  • CLASSES

    Proton Pump Inhibitors/PPIs

    DEA CLASS

    Rx

    DESCRIPTION

    Proton pump inhibitor (PPI); gastric antisecretory agent.
    Used for GERD, peptic ulcer disease, in combination with antibiotics for the eradication of H. pylori, and for hypersecretory conditions such as ZE syndrome.
    May have less potential for drug interactions, seems to inhibit the CYP2C9 to a lesser degree than omeprazole.

    COMMON BRAND NAMES

    AcipHex, Aciphex Sprinkle

    HOW SUPPLIED

    Aciphex Sprinkle Oral Cap DR Pellets: 5mg, 10mg
    AcipHex/Rabeprazole/Rabeprazole Sodium Oral Tab DR: 20mg

    DOSAGE & INDICATIONS

    For the symptomatic treatment of non-erosive gastroesophageal reflux disease (GERD).
    Oral dosage (delayed-release tablets)
    Adults

    20 mg PO once daily for 4 weeks; if symptoms do not completely resolve after 4 weeks, consider an additional course of treatment. Per treatment guidelines, initiate empiric therapy based on a presumptive diagnosis of GERD in the setting of typical symptoms of heartburn and regurgitation. For patients with partial response to once daily therapy, consider rabeprazole 20 mg PO twice daily or consider a one-time switch to a different PPI. Refer non-responders for further evaluation. Consider maintenance therapy for patients who continue to have symptoms after PPI discontinuation; the lowest effective dose, including on demand or intermittent therapy, should be used with regular assessment of the need for continued PPI therapy. Alternatively, step down maintenance therapy to an H2 blocker is acceptable.

    Children and Adolescents 12 years and older

    20 mg PO once daily for 8 weeks.

    Oral dosage (delayed-release sprinkle capsules)
    Children 1 to 11 years weighing 15 kg or more

    10 mg PO once daily for 12 weeks. A maximum dose of 20 mg PO once daily was used in patients weighing 15 kg or more in a randomized, double-blind study (n = 127, age 1 to 11 years); however the rate of endoscopic/histologic healing was similar in patients receiving the 20 mg dose compared to those receiving the 10 mg dose (78% vs. 76%) and the rate of adverse reactions (vomiting and abdominal pain) thought to be related to rabeprozole was higher in those receiving 20 mg.

    Children 1 to 11 years weighing less than 15 kg

    5 mg PO once daily for 12 weeks, with the option to increase to 10 mg/day if inadequate response.

    For the healing of duodenal ulcer.
    NOTE: For dosing in patients with gastric or duodenal ulcers due to H. pylori, see “H. pylori eradication” indication.
    Oral dosage
    Adults

    20 mg PO once daily in the morning, for up to 4 weeks. Most patients heal within four weeks of rabeprazole therapy; however, some patients require additional therapy.

    For the treatment of erosive esophagitis (erosive GERD).
    Oral dosage (delayed-release tablets)
    Adults

    20 mg PO once daily for 4 to 8 weeks; if the patient does not heal after 8 weeks, consider an additional 8-week course. A higher dose of 40 mg PO per day has been effective in pre-clinical trials of acid peptic diseases including GERD, but was not significantly more effective than 20 mg/day. For severe reflux with ulceration and/or stricture formation, a higher dose regimen of a proton pump inhibitor (e.g., 40 mg/day of rabeprazole) may yield better healing rates. For maintenance of healing, 20 mg PO once daily; periodically reassess need for continued PPI therapy.

    For the treatment of pathological hypersecretory conditions including Zollinger-Ellison syndrome.
    Oral dosage
    Adults

    Initially, 60 mg PO once daily. Dosage requirements vary and should be continued as clinically indicated. Some patients may require divided doses. Doses up to 100 mg PO once daily or 60 mg PO twice daily have been administered. Patients with Zollinger-Ellison syndrome have been treated continuously for up to one year.

    For Helicobacter pylori (H. pylori) eradication in the treatment of patients with duodenal ulcer disease (active or a history of duodenal ulcer), gastric ulcer†, dyspepsia†, or gastric mucosa associated lymphoid tissue (MALT) lymphoma†.
    NOTE: The American College of Gastroenterology (ACG) recommends 10 to 14 days of a triple-drug regimen containing a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole. Although 10 to 14 days is recommended, ACG also indicates that giving therapy for 2 weeks may be preferred; a meta-analysis of more than 900 patients found that, as compared to a 7-day regimen, the rate of H. pylori eradication was significantly higher in patients taking triple therapy for 14 days (odds ratio 0.62, 95% CI 0.45 to 0.84). Although not significant, there was a trend towards improved eradication rates with 10 days of therapy vs. 7 days of therapy. The same combination for 14 days continues to be recommended as first line therapy in the 2006 global updates from the Maastricht III Consensus Report.
    NOTE: In populations where H. pylori infection is common (10% or more), patients presenting with non-ulcer dyspepsia should be tested for H. pylori; those found to be H. pylori positive should be started on combination eradication therapy (also see Prevpac monograph).
    NOTE: A large body of data exist to support the importance of H. pylori eradication as the first line treatment of gastric MALT lymphoma. Following H. pylori eradication, long term tumor regression is observed in 60% to 90% of patients.
    In combination with clarithromycin and amoxicillin in adults.
    Oral dosage
    Adults

    The FDA approved regimen is 20 mg PO twice daily with amoxicillin (1,000 mg twice daily) and clarithromycin (500 mg twice daily) for 7 days; administer with the morning and evening meals. The ACG recommends treatment for 10 to 14 days.

    In combination with clarithromycin and metronidazole in adults†.
    Oral dosage
    Adults

    20 mg PO twice daily with clarithromycin (500 mg PO twice daily) and metronidazole (500 mg PO twice daily) for 10 to 14 days is recommended.

    In combination with bismuth, metronidazole, and tetracycline in adults†.
    Oral dosage
    Adults

    20 mg twice daily with bismuth subsalicylate (525 mg PO four times daily), metronidazole (250 mg PO four times daily), and tetracycline (500 mg PO four times daily) for 10 to 14 days is recommended.

    In combination with levofloxacin and amoxicillin in adults†.
    Oral dosage
    Adults

    In one study, a levofloxacin-based triple therapy regimen (levofloxacin 500 mg PO once daily, amoxicillin 1,000 mg PO twice daily, and rabeprazole 20 mg PO once daily for 7 days) was associated with a significantly higher eradication rate (more than 90%) compared to dual therapy (levofloxacin/rabeprazole; eradication rate 70% or less regardless of duration).

    In combination with amoxicillin and metronidazole in pediatric patients†.
    Oral dosage
    Children and Adolescents

    1 to 2 mg/kg/day PO divided twice daily (Max: 20 mg/dose) in combination with amoxicillin (25 mg/kg/dose PO twice daily [Max: 1 g/dose]) and metronidazole (10 mg/kg/dose PO twice daily [Max: 500 mg/dose]) for 1 to 2 weeks.

    In combination with amoxicillin and clarithromycin in pediatric patients†.
    Oral dosage
    Children and Adolescents

    1 to 2 mg/kg/day PO divided twice daily (Max: 20 mg/dose) in combination with amoxicillin (25 mg/kg/dose PO twice daily [Max: 1 g/dose]) and clarithromycin (10 mg/kg/dose PO twice daily [Max: 500 mg/dose]) for 1 to 2 weeks.

    As part of a sequential therapy regimen in pediatric patients†.
    Oral dosage
    Children and Adolescents

    1 to 2 mg/kg/day PO divided twice daily (Max: 20 mg/dose) for 10 days; use in combination with amoxicillin (25 mg/kg/dose PO twice daily [Max: 1 g/dose]) for days 1 through 5, and then clarithromycin (10 mg/kg/dose PO twice daily [Max: 500 mg/dose]) and metronidazole (10 mg/kg/dose PO twice daily [Max: 500 mg/dose]) for days 6 through 10.

    For the short-term treatment of frequent dyspepsia† or pyrosis (heartburn)† that occurs >= 2 times per week.
    Oral dosage
    Adults

    20 mg PO once daily for up to 14 days. Full relief may take 1—4 days. Reassess if heartburn returns after the 14-day treatment regimen.

    For the healing of gastric ulcer†.
    NOTE: For dosing in patients with gastric or duodenal ulcers due to H. pylori, see “H. pylori eradication” indication.
    Oral dosage
    Adults

    20 mg PO once daily in the morning for 3—6 weeks. Healing of gastric ulcers with proton pump inhibitors generally takes longer than duodenal ulcers and may require 4—8 weeks of therapy.

    For the treatment of proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) in the differential diagnosis of eosinophilic esophagitis (EoE)†.
    Oral dosage
    Adults

    PPI dosing in the range of 20—40 mg PO twice daily 30—60 minutes before meals has been studied; treat for up to 8 weeks and continue until the time of the follow-up endoscopy and biopsy. According to guidelines, a PPI trial is central to the differential diagnosis of EoE. If eosinophilia and symptoms persist on repeat endoscopy and biopsy following a PPI trial, then EoE can be formally diagnosed. If symptoms and eosinophilia resolve, then PPI-REE is diagnosed; PPI-REE patients may or may not have underlying GERD. More than 1/3 of all patients with esophageal eosinophilia on biopsy will respond to a PPI.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO for GERD, duodenal ulcer or gastric ulcer; 120 mg/day PO for Zollinger-Ellison syndrome.

    Geriatric

    40 mg/day PO for GERD, duodenal ulcer or gastric ulcer; 120 mg/day PO for Zollinger-Ellison syndrome.

    Adolescents

    20 mg/day PO is the FDA-approved maximum; however, up to 40 mg/day PO has been used off-label for H. pylori eradication.

    Children

    12 years: 20 mg/day PO is the FDA-approved maximum; however, up to 40 mg/day PO has been used off-label for H. pylori eradication.
    1 to 11 years: 10 mg/day PO (delayed-release capsules) is the FDA-approved maximum; however, up to 2 mg/kg/day PO (Max: 40 mg/day) has been used off-label for H. pylori eradication.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is recommended in patients with mild to moderate hepatic impairment (e.g., cirrhosis). Use rabeprazole with caution in patients with severe hepatic impairment; data are lacking in this subgroup.

    Renal Impairment

    No dosage adjustment is necessary.
     
    Intermittent hemodialysis
    Rabeprazole is extensively protein bound and is not readily hemodialyzable.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Delayed-release tablets:
    Have patient swallow whole; tablets should not be chewed, crushed, or split.
    According to the manufacturer, may be administered without regard to meals ; however guidelines suggest to administer on an empty stomach, 30—60 minutes before meals.
     
    Delayed-release capsules (e.g., Aciphex Sprinkle):
    Open capsules (an arrow imprint on the capsule indicates direction for opening the capsule) and sprinkle contents on a spoonful of soft food (e.g. apple sauce, fruit or vegetable based baby food, or yogurt) or liquid (e.g. infant formula, apple juice, or pediatric electrolyte solution). The food should be at or below room temperature.
    Whole dose should be taken within 15 minutes of being sprinkled; do not store mixture for future use.
    Administer with this small amount of food or liquid, 30 minutes before a meal.

    STORAGE

    AcipHex:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Aciphex Sprinkle:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Antimicrobials, proton pump inhibitors, and bismuth preparations suppress Helicobacter pylori. Ingestion of these substances within four weeks prior to performing urease or breath-tests for H. pylori detection may lead to false negative results. In the four weeks prior to performing the test, the patient should avoid the use of rabeprazole and other agents which are known to suppress H. pylori.

    Proton pump inhibitors (PPIs) hypersensitivity

    Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole or other substituted benzimidazoles such as omeprazole or lansoprazole (i.e., known proton pump inhibitors (PPIs) hypersensitivity). There has been evidence of PPI cross-sensitivity in some sensitive individuals in literature reports. Although rare, occasionally such reactions can be serious (i.e., result in anaphylaxis, angioedema, or acute interstitial nephritis).

    Hepatic disease

    Rabeprazole elimination half-life may be significantly prolonged in patients with hepatic disease (see Pharmacokinetics); however, no dosage adjustment is recommended in patients with mild to moderate hepatic impairment. Patients with severe hepatic disease may require dosage reduction.

    Diarrhea, pseudomembranous colitis

    The use of gastric acid suppressive therapy, such as PPIs, may increase the risk of enteric infection by encouraging the growth of gut microflora and increasing susceptibility to organisms including Salmonella, Campylobacter jejuni, Escherichia coli, Clostridium difficile, Vibrio cholerae, and Listeria. A systematic review examined the relationship between PPI use and susceptibility to enteric infections and found enhanced susceptibility for Salmonella infections (adjusted RR range: 4.2—8.3 in 2 studies), Campylobacter (RR 3.5—11.7 in 4 studies) and C. difficile infections (RR 1.2—5.0 in 17 out of 27 studies). In particular, PPI use has been linked to an increased risk of Clostridium difficile–associated diarrhea (CDAD). A diagnosis of CDAD should be considered for patients taking PPIs who develop diarrhea that does not improve. Advise patients to seek immediate care from a healthcare professional if they experience watery stool that does not go away, abdominal pain, and fever while taking PPIs. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. The PPIs, including rabeprazole, are recommended for use in combination with certain antibiotics to eradicate Helicobacter pylori. Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents in combination with PPIs.

    Gastric cancer

    Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric cancer or other malignancy.

    Vitamin B12 deficiency

    Daily treatment with gastric acid-suppressing medication such as rabeprazole over a long period of time (e.g., > 3 years) may lead to malabsorption of cyanocobalamin and vitamin B12 deficiency. Cases of cyanocobalamin deficiency occurring with acid-suppression therapy have been reported in the literature. One large case-controlled study compared patients with and without an incident diagnosis of vitamin B12 deficiency. A correlation was demonstrated between vitamin B12 deficiency and gastric acid-suppression therapy of > 2 years duration [i.e., proton pump inhibitor (PPI), H2-receptor antagonist]. In addition, a dose-dependant relationship was evident, as larger daily PPI pill counts were more strongly associated with vitamin B12 deficiency. The possibility of cyanocobalamin deficiency should, therefore, be considered if clinical symptoms are observed.

    Bone fractures, geriatric, osteoporosis

    Use proton pump inhibitors (PPIs) in patients with or who have risk factors for osteoporosis cautiously. PPIs have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. Epidemiological studies have reported an increased risk of fractures with the use of PPIs; the studies compared claims data of patients treated with PPIs versus individuals who were not using PPIs. The risk of fracture was increased in patients who received high-dose (defined as multiple daily doses or doses greater than those recommended in non-prescription use), and long-term PPI therapy (a year or longer); fractures were primarily observed in older adult and geriatric patients 50 years of age and older. It should be noted that pre-approval randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; however, these RCTs were of shorter study duration (generally 6 months or less). When prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients with or at risk for osteopenia or osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation. According to the Beers Criteria, PPIs are considered potentially inappropriate medications (PIMs) for use in geriatric patients due to the risk of Clostridium difficile and bone loss/fractures. Scheduled use for more than 8 weeks should be avoided except for high-risk patients (e.g., oral corticosteroids or chronic NSAID use), erosive esophagitis, Barrett's esophagitis, pathological hypersecretory condition, or demonstrated need for maintenance treatment (e.g., due to failure of drug discontinuation trial or H-2 blockers). The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, the indication for use of a proton pump inhibitor should be based on clinical symptoms and/or endoscopic findings. During use to treat or prevent NSAID-induced gastritis or esophagitis, there should be documentation that analgesics with less GI toxicity than NSAIDs have been tried or were not indicated. If used for longer than 12 weeks, clinical rationale for continued need and/or documentation should support an underlying chronic disease (e.g., GERD) or risk factors (e.g., chronic NSAID use). Adverse consequences of medication therapy include new or worsening headaches, nausea, emesis, flatulence, difficulty swallowing, abdomen pain, diarrhea, or other GI symptoms. In addition, PPIs may increase the risk of clostridium difficile colitis.

    Hypomagnesemia, long QT syndrome

    Daily treatment with a gastric acid-suppressing medication over a long period of time (e.g., 3 months to > 1 year) may lead to hypomagnesemia; cases have been reported in patients taking rabeprazole. Generally, hypomagnesemia is corrected with magnesium supplementation; however, in cases where hypomagnesemia is observed during PPI administration, discontinuation of the PPI may also be necessary. Low serum magnesium may lead to serious adverse events such as muscle spasm (tetany), seizures, and irregular heartbeat (arrhythmias). Use PPIs with caution and, if possible, avoid long-term (> 14 days) use in patients with congenital long QT syndrome, as they may be at higher risk for arrhythmias. In pediatric patients, irregular heartbeat may cause fatigue, upset stomach, dizziness, and lightheadedness. For patients expected to be on PPI therapy for a prolonged period of time, it is prudent for clinicians to obtain serum magnesium concentrations prior to initiating PPI therapy as well as throughout treatment. Patients on concomitant medications such as digoxin or diuretics may also require periodic monitoring of serum magnesium.

    Rebound acid hypersecretion

    Studies suggest that long-term PPI therapy is associated with a temporal increase in gastric acid secretion shortly following treatment discontinuation. A similar and well established response has been noted after withdrawal of H2 blockers. Profound gastric acid suppression during PPI therapy leads to a drug-induced reflex hypergastrinemia and subsequent rebound acid hypersecretion. In this hypersecretory state, enterochromaffin-like cell hypertrophy also results in a temporal increase in serum chromogranin A (CgA) levels. It is unclear, however, if this hypersecretory reflex results in clinically significant effects in patients on or attempting to discontinue PPI therapy. A clinically significant effect may lead to gastric acid-related symptoms upon PPI withdrawal and possible therapy dependence. Studies in healthy subjects (H. pylori negative) as well as GERD patients, present conflicting data regarding whether PPI therapy beyond 8-weeks is associated with rebound acid hypersecretion and associated dyspeptic symptoms shortly following PPI cessation. Until more consistent study results shed light on this possible effect, it is prudent to follow current treatment guidelines employing the lowest effective dose, for the shortest duration of time in symptomatic patients. For patients requiring maintenance therapy, consider on demand or intermittent PPI therapy, step down therapy to an H2 blocker, and regularly assess the need for continued gastric suppressive therapy.

    Pregnancy

    There are no adequate and well-controlled studies in pregnant women and no reports describing the use of rabeprazole during pregnancy in humans; changes in bone morphology have been observed in the offspring of animals treated with higher than human doses of a differnt PPI on a body surface area basis. The low molecular weight of rabeprazole (381) suggests that the drug will pass to the fetus. Human pregnancy experience with other PPIs (i.e., omeprazole and lansoprazole) have not shown a casual relationship with congenital malformations; however, there is a possibility that the true risk of malformation was missed due to study design and/or sample size. In the absence of sound exposure data, rabeprazole should be used during pregnancy only when clearly needed. If rabeprazole is required, it is best to avoid 1st trimester exposure. If inadvertent exposure does occur during the first 3 months of pregnancy, the known congenital risk for the fetus appears to be low. In 2009, a population-based observational cohort study explored a possible link between gastric acid suppressive therapy (e.g., proton pump inhibitors) during pregnancy and a diagnosis of allergic disease or a prescription for asthma or allergy medications in the exposed child. Among the cohort (n = 585,716), 1% of children exposed to gastric acid suppressive drugs in pregnancy received a diagnosis of allergic diease. For developing allergy or asthma, an increased OR of 1.43 and 1.51, respectively, were observed regardless of drug used, time of exposure during pregnancy, and maternal history of disease. Proposed possible mechanisms for a link include: (1) exposure to increased amounts of allergens could cause sensitization to digestion-labile antigens in the fetus; (2) the maternal Th2 cytokine pattern could promote an allergy prone phenotype in the fetus; (3) maternal allergen specific immunoglobulin could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Study limitations were present and confirmation of results are necessary before further conclusions can be drawn from this data. Risk versus benefit should be considered prior to use.

    Breast-feeding

    It is not known whether rabeprazole is excreted into human breast milk. It is excreted into the milk of lactating rats; nursing pups exposed to rabeprazole had decreased weight gain after the drug was administered in late gestation and lactation. The clinical significance of this in humans is unknown. Since other PPIs are excreted in human milk, rabeprazole is expected to do so. Because of the potential for serious adverse reactions from rabeprazole in a breast-fed infant (including suppression of gastric acid secretion), a decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother's condition. Alternative therapies for consideration include antacids and H2 blockers.

    Infants, neonates

    Per the manufacturer, clinical studies conducted do not support the use of rabeprazole for the treatment of GERD in infants younger than 1 year of age. Use of rabeprazole in neonates is strongly discouraged at this time for the treatment of GERD, based on the risk of prolonged acid suppression and lack of demonstrated safety and effectiveness in neonates.

    Systemic lupus erythematosus (SLE)

    Use with caution in patients with a history of systemic lupus erythematosus (SLE) as rabeprazole has been reported to activate or exacerbate SLE.

    ADVERSE REACTIONS

    Severe

    hepatic encephalopathy / Delayed / 0-2.0
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    coma / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 2.0-2.0
    hepatitis / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    peripheral edema / Delayed / 0-2.0
    jaundice / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    delirium / Early / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    hyperammonemia / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    headache / Early / 0-9.9
    nausea / Early / 1.8-4.5
    diarrhea / Early / 1.0-4.5
    abdominal pain / Early / 0-3.6
    vomiting / Early / 3.6-3.6
    flatulence / Early / 3.0-3.0
    pharyngitis / Delayed / 3.0-3.0
    xerostomia / Early / 0-2.0
    dizziness / Early / 0-2.0
    infection / Delayed / 2.0-2.0
    myalgia / Early / 0-2.0
    arthralgia / Delayed / 0-2.0

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Acetaminophen; Butalbital; Caffeine: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Acetaminophen; Butalbital; Caffeine; Codeine: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Alendronate: Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
    Alendronate; Cholecalciferol: Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Aliskiren; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amiloride; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amobarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Amphetamine: Patients receiving amphetamine; dextroamphetamine or extended-release amphetamine; dextroamphetamine with a proton pump inhibitor should be monitored for changes in clinical efficacy. Proton pump inhibitors (PPIs) may alter the pharmacokinetics of amphetamine; dextroamphetamine due to a reduction in gastric acidity. An interaction has been noted with the extended-release product (Adderall XR) when administered with a PPI. Co-administration of Adderall XR 20 mg and omeprazole 40 mg resulted in a decrease in median Tmax of d-amphetamine and l-amphetamine by 1.25 hours and 2.5 hours, respectively, compared to administration of Adderall XR alone.The AUC and maximal concentration (Cmax) of each moiety were unaffected.
    Amphetamine; Dextroamphetamine Salts: Patients receiving amphetamine; dextroamphetamine or extended-release amphetamine; dextroamphetamine with a proton pump inhibitor should be monitored for changes in clinical efficacy. Proton pump inhibitors (PPIs) may alter the pharmacokinetics of amphetamine; dextroamphetamine due to a reduction in gastric acidity. An interaction has been noted with the extended-release product (Adderall XR) when administered with a PPI. Co-administration of Adderall XR 20 mg and omeprazole 40 mg resulted in a decrease in median Tmax of d-amphetamine and l-amphetamine by 1.25 hours and 2.5 hours, respectively, compared to administration of Adderall XR alone.The AUC and maximal concentration (Cmax) of each moiety were unaffected.
    Amphetamine; Dextroamphetamine: Patients receiving amphetamine; dextroamphetamine or extended-release amphetamine; dextroamphetamine with a proton pump inhibitor should be monitored for changes in clinical efficacy. Proton pump inhibitors (PPIs) may alter the pharmacokinetics of amphetamine; dextroamphetamine due to a reduction in gastric acidity. An interaction has been noted with the extended-release product (Adderall XR) when administered with a PPI. Co-administration of Adderall XR 20 mg and omeprazole 40 mg resulted in a decrease in median Tmax of d-amphetamine and l-amphetamine by 1.25 hours and 2.5 hours, respectively, compared to administration of Adderall XR alone.The AUC and maximal concentration (Cmax) of each moiety were unaffected.
    Ampicillin: Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
    Ampicillin; Sulbactam: Proton pump inhibitors (PPIs) have long-lasting effects on the secretion of gastric acid. For enteral ampicillin, whose bioavailability is influenced by gastric pH, the concomitant administration of PPIs can exert a significant effect on ampicillin absorption.
    Anticholinergics: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Aprepitant, Fosaprepitant: Use caution if rabeprazole and aprepitant, fosaprepitant are used concurrently and monitor for an increase in rabeprazole-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rabeprazole is a CYP3A4 substrate in vitro. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of rabeprazole. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aspirin, ASA; Butalbital; Caffeine: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Atazanavir: Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%.
    Atazanavir; Cobicistat: Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. Use caution when administering cobicistat and rabeprazole concurrently. Cobicistat is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Atenolol; Chlorthalidone: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Atropine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Difenoxin: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Diphenoxylate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Edrophonium: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate. The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Axitinib: Monitor patients for increased axitinib-related adverse events if coadministration with rabeprazole occurs. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Rabeprazole is a CYP2C19 inhibitor in vitro. Theoretically, exposure to axitinib may be increased. While the aqueous solubility of axitinib is pH dependent, with higher pH resulting in lower solubility, this effect was not significant when studied with rabeprazole; dosage adjustments are not recommended with proton pump inhibitors.
    Azilsartan; Chlorthalidone: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Barbiturates: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate. The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Belladonna; Opium: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Benazepril; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Bendroflumethiazide; Nadolol: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Benztropine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Bisacodyl: The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
    Bisoprolol; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Boceprevir: Close clinical monitoring is advised when administering rabeprazole with boceprevir due to an increased potential for rabeprazole-related adverse events. If rabeprazole dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of rabeprazole. Rabeprazole is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated rabeprazole plasma concentrations.
    Bortezomib: Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Bosutinib: Concomitant use of bosutinib and proton-pump inhibitors, such as rabeprazole, may result in decreased plasma exposure of bosutinib. Consider using a short-acting antacid or H2 blocker if acid suppression therapy is needed; separate the administration of bosutinib and antacids or H2-blockers by more than 2 hours.
    Budesonide: Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
    Budesonide; Formoterol: Enteric-coated budesonide granules dissolve at a pH greater than 5.5. Concomitant use of budesonide oral capsules and drugs that increase gastric pH levels can cause the coating of the granules to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
    Bumetanide: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Butabarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Calcium Carbonate; Risedronate: Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use PPIs in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
    Candesartan; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Captopril; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Carbamazepine: Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Carbamazepine induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If carbamazepine and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Cefpodoxime: Cefpodoxime proxetil requires a low gastric pH for dissolution; therefore, concurrent administration with medications that increase gastric pH, such as proton pump inhibitors (PPIs) may decrease the bioavailability of cefpodoxime. When cefpodoxime was administered with high doses of antacids and H2-blockers, peak plasma concentrations were reduced by 24% and 42% and the extent of absorption was reduced by 27% and 32%, respectively. The rate of absorption is not affected.
    Ceftibuten: Coadministration of 150 mg of ranitidine every 12 hours for 3 days increased the ceftibuten Cmax by 23 percent and ceftibuten AUC by 16 percent. Based on this information, increased gastric pH caused by PPIs may possibly affect the kinetics of ceftibuten.
    Cefuroxime: Avoid the concomitant use of proton pump inhibitors (PPIs) and cefuroxime. Drugs that reduce gastric acidity, such as PPIs, can interfere with the oral absorption of cefuroxime axetil and may result in reduced antibiotic efficacy.
    Ceritinib: Use caution if coadministration of ceritinib with rabeprazole is necessary, as the bioavailability of ceritinib may be reduced. Ceritinib displays pH-dependent solubility with decreased solubility at a higher pH, but data are conflicting regarding clinical significance. In healthy subjects, the AUC and Cmax of ceritinib decreased by 76% and 79%, respectively, when a single dose was administered with esomeprazole. However, in a subgroup of patients with NSCLC from a multicenter, open-label clinical trial, the AUC and Cmax of ceritinib decreased by 30% and 25%, respectively, after a single dose was administered with proton pump inhibitors; there was no clinically meaningful effect on ceritinib exposure at steady state.
    Chlordiazepoxide; Clidinium: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Chlorothiazide: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Chlorthalidone: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Chlorthalidone; Clonidine: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Citalopram: The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with rabeprazole, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors.
    Clobazam: A dosage reduction of clobazam may be necessary during co-administration of rabeprazole. Metabolism of the active metabolite of clobazam occurs primarily through CYP2C19 and rabeprazole is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
    Clopidogrel: Use clopidogrel and rabeprazole together with caution as it may reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. The American College of Cardiology Foundation (ACCF), American College of Gastroenterology (ACG) and American Heart Association (AHA) state that routine use of proton pump inhibitor (PPI) therapy is not recommended for patients at lower risk of gastrointestinal bleed but should be considered in those at high risk, such as those with a history of gastrointestinal bleed. Clinicians should carefully assess the risks and benefits of PPI use in patients on clopidogrel therapy and administration should be based on clinical need. If necessary, consider using a PPI medication with less pronounced effects on antiplatelet activity, such as rabeprazole; omeprazole and esomeprazole should be avoided. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. All PPIs are CYP219 substrates, and, to varying extents, are also inhibitors; thus, it is possible that any PPI may decrease the conversion of clopidogrel to its active metabolite, thereby reducing its effectiveness.
    Cobicistat: Use caution when administering cobicistat and rabeprazole concurrently. Cobicistat is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Use caution when administering cobicistat and rabeprazole concurrently. Cobicistat is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Use caution when administering cobicistat and rabeprazole concurrently. Cobicistat is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Cyanocobalamin, Vitamin B12: Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Cyclosporine: Rabeprazole may inhibit the metabolism of cyclosporine, a CYP3A4 substrate.
    Cysteamine: Monitor white blood cell (WBC) cystine concentration closely when administering delayed-release cysteamine (Procysbi) with proton pump inhibitors (PPIs). Drugs that increase the gastric pH may cause the premature release of cysteamine from delayed-release capsules, leading to an increase in WBC cystine concentration. Concomitant administration of omeprazole 20 mg did not alter the pharmacokinetics of delayed-release cysteamine when administered with orange juice; however, the effect of omeprazole on the pharmacokinetics of delayed-release cysteamine when administered with water have not been studied.
    Dabrafenib: Proton pump inhibitors (PPIs) elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and PPIs may reduce the systemic exposure and bioavailability of dabrafenib. No formal trials have been performed to evaluate this interaction and it is not known how this interaction affects the efficacy of dabrafenib.
    Darifenacin: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Darunavir; Cobicistat: Use caution when administering cobicistat and rabeprazole concurrently. Cobicistat is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Concurrent administration of rabeprazole with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together. Concurrent administration of rabeprazole with ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together.
    Dasatinib: Although not specifically studied, long-term suppression of gastric acid secretion by proton pump inhibitors (PPIs) is also likely to decrease the exposure to dasatinib. The concomitant use these agents is not recommended. For example, in a study of 24 healthy subjects, administration of a single 50 mg dose of dasatinib 10 hours after famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. Because separating the administration of dasatinib and antacids by at least 2 hours minimizes the interaction, the use of antacids should be considered in place of PPIs in patients receiving dasatinib therapy.
    Delavirdine: Because proton pump inhibitors (PPIs) increase gastric pH, decreased delavirdine absorption may occur. However, since these agents affect gastric pH for an extended period, separation of doses may not eliminate the interaction. Chronic use of PPIs with delavirdine is not recommended.
    Dexmethylphenidate: The effects of gastrointestinal pH alterations on the absorption of methylphenidate extended release capsules (Ritalin LA) and dexmethylphenidate extended-release tablets (Focalin XR) have not been studied. Although the SODAS system (drug delivery system utilized in Ritalin LA and Focalin XR) is thought to be minimally affected by changes in pH, per the manufacturer, the modified release characteristics of both extended-release formulations are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of dexmethylphenidate or methylphenidate. Patients receiving these extended-release products (Focalin XR or Ritalin LA) with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Dextroamphetamine: Patients receiving amphetamine; dextroamphetamine or extended-release amphetamine; dextroamphetamine with a proton pump inhibitor should be monitored for changes in clinical efficacy. Proton pump inhibitors (PPIs) may alter the pharmacokinetics of amphetamine; dextroamphetamine due to a reduction in gastric acidity. An interaction has been noted with the extended-release product (Adderall XR) when administered with a PPI. Co-administration of Adderall XR 20 mg and omeprazole 40 mg resulted in a decrease in median Tmax of d-amphetamine and l-amphetamine by 1.25 hours and 2.5 hours, respectively, compared to administration of Adderall XR alone.The AUC and maximal concentration (Cmax) of each moiety were unaffected.
    Diclofenac; Misoprostol: The effectiveness of proton pump inhibitors may be decreased if given with other antisecretory agents including misoprostol. Proton pump inhibitors inhibit only actively secreting H+-pumps.
    Dicyclomine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Digoxin: Rabeprazole or other proton pump inhibitors (PPIs) can affect digoxin absorption due to their long-lasting effect on gastric acid secretion. Additionally, PPIs may slightly increase digoxin bioavailability. When rabeprazole was co-administered with digoxin, the AUC and Cmax for digoxin increased 19% and 29%, respectively. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Dronedarone: Dronedarone is metabolized by and is an inhibitor of CYP3A. Rabeprazole is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Enalapril; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Eprosartan; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Erlotinib: Avoid coadministration of rabeprazole with erlotinib if possible due to the risk of decreased efficacy of erlotinib. Erlotinib solubility is pH dependent and solubility decreases as pH increases. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract, like proton pump inhibitors (PPIs), may decrease the absorption of erlotinib. Concomitant use of erlotinib and omeprazole, a PPI, decreased erlotinib AUC and Cmax by 46% and 61% respectively. Increasing the dose of erlotinib may not compensate for the loss of exposure. Proton-pump inhibitors exert their effect over an extended amount of time, as a result spacing of doses is also not expected to eliminate the interaction. Substitution of antacids, separated from the erlotinib dose by several hours, may be considered. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics.
    Escitalopram: The plasma concentration of escitalopram, a CYP2C19 substrate, may be increased when administered concurrently with rabeprazole, a CYP2C19 inhibitor. If these drugs are used together, monitor for escitalopram-associated adverse reactions.
    Eslicarbazepine: Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of rabeprazole; both enzymes are involved in the metabolism of proton pump inhibitors (PPIs). It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and PPIs. If eslicarbazepine and PPI must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Ethacrynic Acid: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Fenofibric Acid: At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as rabeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of rabeprazole during coadministration with fenofibric acid.
    Fesoterodine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Flavoxate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Flibanserin: The concomitant use of flibanserin and strong CYP2C19 inhibitors, such as proton pump inhibitors (PPIs), may increase flibanserin concentrations, resulting in severe hypotension, syncope, and/or CNS depression. Therefore, patients should be monitored for flibanserin-induced adverse reactions, and the risks of combination therapy should be discussed with the patient. In addition, the concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including pantoprazole, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions.
    Fosinopril; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Furosemide: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Gefitinib: If possible, avoid the concomitant use of gefitinib with rabeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of rabeprazole. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Glycopyrrolate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Glycopyrrolate; Formoterol: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Homatropine; Hydrocodone: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Hydantoins: Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Phenytoin induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs (e.g., CYP3A4, CYP2C19). A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If phenytoin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Hydralazine; Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Irbesartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Lisinopril: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Losartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Methyldopa: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Metoprolol: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Moexipril: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Olmesartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Propranolol: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Quinapril: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Spironolactone: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Telmisartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Triamterene: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hydrochlorothiazide, HCTZ; Valsartan: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Hyoscyamine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Idelalisib: Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with rabeprazole, a CYP3A substrate, as rabeprazole toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Indacaterol; Glycopyrrolate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Iron: The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of proton pump inhibitors can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. Proton pump inhibitors have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
    Isavuconazonium: Concomitant use of isavuconazonium with rabeprazole may result in increased serum concentrations of rabeprazole. Rabeprazole is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Some manufacturers recommend avoiding the coadministration of rifampin and proton pump inhibitors (PPIs). Rifamycins induce multiple hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If rifampin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Isoniazid, INH; Rifampin: Some manufacturers recommend avoiding the coadministration of rifampin and proton pump inhibitors (PPIs). Rifamycins induce multiple hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If rifampin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Itraconazole: Itraconazole oral bioavailability requires an acidic environment for solubility. Proton pump inhibitors (PPIs) have been shown to reduce plasma concentrations of itraconazole. The interaction with antacids may be avoided by staggering the administration time with itraconazole. However, due to the sustained action of proton pump inhibitors (PPIs), a drug interaction may still occur even if administration times are adjusted. Proton pump inhibitors (PPIs) should be withheld or avoided in patients requiring oral itraconazole therapy.
    Ivacaftor: Use caution when administering ivacaftor and rabeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Ledipasvir; Sofosbuvir: Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with proton pump inhibitors (PPIs) may result in lower ledipasvir plasma concentrations. Ledipasvir can be administered with PPIs if given simultaneously under fasting conditions. The PPI dose should not exceed a dose that is comparable to omeprazole 20 mg/day.
    Loop diuretics: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Lopinavir; Ritonavir: Concurrent administration of rabeprazole with ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together.
    Luliconazole: Theoretically, luliconazole may increase the side effects of rabeprazole, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of rabeprazole, such as GI effects. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: Lumacaftor; ivacaftor may reduce the efficacy of rabeprazole by decreasing its systemic exposure; monitor for therapeutic efficacy. Rabeprazole is a substrate of CYP3A4 and CYP2C19. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor may also induce CYP2C19.
    Lumacaftor; Ivacaftor: Use caution when administering ivacaftor and rabeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Mefloquine: Proton pump inhibitors (PPIs) may increase plasma concentrations of mefloquine. Patients on chronic mefloquine therapy might be at increased risk of adverse reactions, especially patients with a neurological or psychiatric history.
    Mepenzolate: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Mephobarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Mesalamine, 5-ASA: The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like proton pump inhibitors.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Methohexital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Methotrexate: Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs). Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs such as omeprazole, pantoprazole, or esomeprazole with methotrexate primarily at high dose may elevate and prolong serum methotrexate concentrations and/or its metabolite hydroxymethotrexate, which may lead to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was coadministered with PPIs but was not observed when methotrexate was coadministered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. Among adults who received high-dose methotrexate (median dose of 3500 mg/m2, range of 1000-5000 mg/m2), coadministration of PPIs such as omeprazole, lansoprazole, or rabeprazole was identified as a risk factor for delayed methotrexate elimination with an OR of 2.65 (95% confidence interval 1.036.82). The interaction may be partially explained by the inhibitory effects of PPIs on breast cancer resistance protein (BCRP, ABCG2) -mediated methotrexate transport. Altered methotrexate elimination may not be present or problematic among patients who receive lower methotrexate doses. For example, coadministration of lansoprazole 30 mg daily and naproxen 500 mg twice daily for 7 days to recipients of stable oral methotrexate doses (7.515 mg/week) for a minimum of 3 months did not alter the pharmacokinetic profile of either methotrexate or 7-hydroxymethotrexate. Specifically, the peak plasma concentration and area under the plasma concentration-time curve of methotrexate and 7-hydroxymethotrexate were within the 0.80 to 1.25 boundaries.
    Methscopolamine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Methyclothiazide: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Methylphenidate: The effects of gastrointestinal pH alterations on the absorption of methylphenidate extended release capsules (Ritalin LA) and dexmethylphenidate extended-release tablets (Focalin XR) have not been studied. Although the SODAS system (drug delivery system utilized in Ritalin LA and Focalin XR) is thought to be minimally affected by changes in pH, per the manufacturer, the modified release characteristics of both extended-release formulations are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of dexmethylphenidate or methylphenidate. Patients receiving these extended-release products (Focalin XR or Ritalin LA) with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Metolazone: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Misoprostol: The effectiveness of proton pump inhibitors may be decreased if given with other antisecretory agents including misoprostol. Proton pump inhibitors inhibit only actively secreting H+-pumps.
    Mitotane: Use caution if mitotane and rabeprazole are used concomitantly, and monitor for decreased efficacy of rabeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and rabeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of rabeprazole.
    Modafinil: Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Modafinil induces hepatic cytochrome P-450 enzyme CYP3A4 but significantly inhibits CYP2C19; both of these enzymes are responsible for the metabolism of PPIs. It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. If modafinil and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Mycophenolate: Concomitant administration of proton pump inhibitors (PPIs) with mycophenolate mofetil (Cellcept) appears to reduce MPA exposure AUC-12h (25.8 +/- 6.4 mg/L x h with omeprazole vs. 33.3 +/- 11.5 mg//L x h without omeprazole); however, the interaction does not appear to exist with mycophenolate sodium delayed-release tablets (Myfortic). Reduced systemic exposure of MPA after mycophenolate mofetil in the presence of a PPI appears to be due to impaired absorption of mycophenolate mofetil which may occur because of incomplete dissolution of mycophenolate mofetil in the stomach at elevated pH. The clinical significance of reduced MPA exposure is unknown; however patients should be evaluated periodically if mycophenolate mofetil is administered with a PPI. Of note, MPA concentrations appear to be reduced in the initial hours after mycophenolate mofetil receipt but increase later in the dosing interval because of enterohepatic recirculation. A second peak in the concentration-time profile of MPA is observed 612 hours after dosing due to enterohepatic recirculation. For example, the 12-hour plasma concentrations of MPA were similar among patients who received mycophenolate mofetil with or without omeprazole. The biphasic plasma concentration-time course of MPA due to extensive enterohepatic circulation hampers therapeutic drug monitoring of MPA. Drug exposure as measured by AUC-12h is the best estimator for the clinical effectiveness of mycophenolate, but measurement of full-dose interval MPA AUC-12h requires collection of multiple samples over a 12-hour period; MPA predose concentrations correlate poorly with MPA AUC-12h. The interaction does not appear to exist with Mycophenolate sodium (Myfortic).
    Nelfinavir: Use of proton pump inhibitors with nelfinavir is not recommended. Coadministration may result in decreased nelfinavir exposure, subtherapeutic antiretroviral activity, and possibility resistant HIV mutations. In one study, concurrent use of nelfinavir with omeprazole resulted in decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%, respectively.
    Nilotinib: Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Octreotide: The effectiveness of proton pump inhibitors may be decreased if given with other antisecretory agents, such as octreotide. Proton pump inhibitors inhibit only actively secreting H+-pumps. Antacids may be used while taking esomeprazole.
    Ombitasvir; Paritaprevir; Ritonavir: Concurrent administration of rabeprazole with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together. Concurrent administration of rabeprazole with ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together.
    Oritavancin: Coadministration of oritavancin and rabeprazole may result in increases or decreases in rabeprazole exposure and may increase side effects or decrease efficacy of rabeprazole. Rabeprazole is metabolized by CYP3A4 and CYP2C19. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C19. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Oxcarbazepine: Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Oxcarbazepine and its MHD metabolite induce hepatic cytochrome P-450 enzyme CYP3A4 but potently display dose-dependent CYP2C19 inhibition; both enzymes are involved in the metabolism of PPIs. It is unclear that the theoretical interaction would result in a net increase or decrease in PPI action. If oxcarbazepine and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy, or for signs of PPI side effects.
    Oxybutynin: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Pazopanib: Pazopanib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of pazopanib and proton pump inhibitors (PPIs) that elevate the gastric pH may reduce the bioavailability of pazopanib. In a study of patients with solid tumors, the AUC and Cmax of pazopanib were decreased by approximately 40% when coadministered with esomeprazole. If a drug is needed to raise the gastric pH, consider use of a short-acting antacid; separate antacid and pazopanib dosing by several hours.
    Pentobarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Phenobarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Polyethylene Glycol; Electrolytes; Bisacodyl: The concomitant use of bisacodyl oral tablets with drugs that raise gastric pH like proton pump inhibitors can cause the enteric coating of the bisacodyl tablets to dissolve prematurely, leading to possible gastric irritation or dyspepsia. When taking bisacodyl tablets, it is advisable to avoid PPIs within 1 hour before or after the bisacodyl dosage.
    Ponatinib: Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as rabeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Posaconazole: The concurrent use of posaconazole oral suspension and proton pump inhibitors (PPIs) should be avoided, if possible, due to the potential for decreased posaconazole efficacy. If used in combination, closely monitor for breakthrough fungal infections. PPIs increase gastric pH, resulting in decreased posaconazole absorption and lower posaconazole plasma concentrations. When a single 400 mg dose of posaconazole oral suspension was administered with esomeprazole (40 mg PO daily), the mean reductions in Cmax were 46% and the mean reductions in AUC were 32% for posaconazole. The pharmacokinetics of posaconazole delayed-release tablets are not significantly affected by PPIs. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of many PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole). Coadministration may result in increased plasma concentration of the PPIs.
    Primidone: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Propantheline: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Raltegravir: The manufacturer of raltegravir suggests that no dose adjustment for raltegravir is necessary when given concomitantly with agents that increase gastric pH. Coadministration of products that increase gastric pH, such as proton pump inhibitors (PPIs), may increase raltegravir concentrations due to increased raltegravir solubility at higher pH levels.The ratio of the AUC for raltegravir given with and without omeprazole was 3.12 (90% CI 2.13, 4.56).
    Rifabutin: Some manufacturers recommend avoiding the coadministration of rifampin and proton pump inhibitors (PPIs). Rifamycins induce multiple hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If rifampin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Rifampin: Some manufacturers recommend avoiding the coadministration of rifampin and proton pump inhibitors (PPIs). Rifamycins induce multiple hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If rifampin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Rifamycins: Some manufacturers recommend avoiding the coadministration of rifampin and proton pump inhibitors (PPIs). Rifamycins induce multiple hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If rifampin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Rifapentine: Some manufacturers recommend avoiding the coadministration of rifampin and proton pump inhibitors (PPIs). Rifamycins induce multiple hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If rifampin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Rilpivirine: Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
    Risedronate: Use of proton pump inhibitors (PPIs) with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets. In healthy subjects who received esomeprazole for 6 days, the Cmax and AUC of a single dose of risedronate delayed-release tablets (Atelvia) increased by 60% and 22%, respectively. PPIsare widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use PPIs in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. Study results suggest that the interaction may occur across the class; however, other interactions have not been confirmed and data suggest that fracture protection is not diminished when risedronate is used with PPIs. A post hoc analysis of patients who took risedronate 5 mg daily during placebo-controlled clinical trials determined that risedronate significantly reduced the risk of new vertebral fractures compared to placebo, regardless of concomitant PPI use. PPI users (n = 240) and PPI non-users (n = 2489) experienced fracture risk reductions of 57% (p = 0.009) and 38% (p < 0.001), respectively.
    Ritonavir: Concurrent administration of rabeprazole with ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together.
    Saquinavir: Coadministration with omeprazole results in significantly increased saquinavir concentrations. A similar interaction is expected with all proton pump inhibitors (PPIs). If saquinavir must be administered with PPIs, the patient should be closely monitored for saquinavir-related toxicities, including gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis (DVT). Coadministration with omeprazole results in significantly increased saquinavir concentrations. In a small study, 18 healthy individuals received saquinavir 1000 mg (with ritonavir 100 mg) twice daily for 15 days; on days 11 through 15 omeprazole 40 mg was given once daily, which resulted in an 82% increase in the saquinavir AUC. A similar interaction is expected with all PPIs.
    Scopolamine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Secobarbital: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Secretin: Discontinue use of proton pump inhibitors before administering secretin. Patients who are receiving proton pump inhibitors at the time of stimulation testing may be hyperresponsive to secretin stimulation, falsely suggesting gastrinoma. The time required for serum gastrin concentrations to return to baseline after discontinuation of a proton pump inhibitor is specific to the individual drug.
    Simeprevir: Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of rabeprazole, which is a CYP3A4 substrate. Monitor patients for adverse effects of rabeprazole, such as GI effects.
    Sofosbuvir; Velpatasvir: Coadministration of proton pump inhibitors (PPIs) with velpatasvir is not recommended. If it is considered medically necessary to coadminister, velpatasvir should be administered with food and taken 4 hours before omeprazole 20 mg. Other PPIs have not been studied; however, it may be prudent to separate the administration of the other PPIs similarly. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
    Solifenacin: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Sorafenib: Sorafenib displays pH-dependent aqueous solubility; therefore, concomitant use of sorafenib and agents that increase the gastric pH, such as proton pump inhibitors (PPIs), may result in decreased plasma exposure of sorafenib. However, there was no clinically significant change in sorafenib exposure following a single oral dose of sorafenib administered after 5 days of omeprazole 40 mg/day. No sorafenib dosage adjustment is necessary.
    St. John's Wort, Hypericum perforatum: Coadministration of St. John's Wort, Hypericum perforatum (300 mg three times daily) for 14 days with a one time dose of omeprazole (20 mg) on day 15 resulted in decreased omeprazole plasma concentrations in healthy subjects. Omeprazole AUC was reduced by approximately 40% in both poor and extensive metabolizers of CYP2C19. The clinical significance of this interaction is not clear; however, due to variations in the amounts of active ingredient in herbal products, the magnitude of this interaction and the resultant clinical effect may vary. St. John's Wort induces both CYP3A4 and CYP2C19 dependent metabolism of omeprazole. Since, proton pump inhibitors (PPIs) are primary substrates of the CYP2C19 enzyme, patients taking St. John's Wort concomitantly with a PPI should be monitored for PPI efficacy.
    Tamoxifen: In vitro, rabeprazole is a CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6 and, to a lesser extent, by CYP2C19 to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, in vitro, rabeprazole is a CYP3A4 substrate; tamoxifen inhibits CYP3A4. Theoretically, concomitant use may result in increased rabeprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known.
    Telaprevir: Close clinical monitoring is advised when administering rabeprazole with telaprevir due to an increased potential for rabeprazole-related adverse events. If rabeprazole dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of rabeprazole. Rabeprazole is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated rabeprazole plasma concentrations.
    Telotristat Ethyl: Use caution if coadministration of telotristat ethyl and rabeprazole is necessary, as the systemic exposure of rabeprazole may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of rabeprazole; consider increasing the dose of rabeprazole if necessary. Rabeprazole is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: Due to the risk for terbinafine related adverse effects, caution is advised when coadministering rabeprazole. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19; rabeprazole is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Theophylline, Aminophylline: Rabeprazole is metabolized by cytochrome P450 enzymes in the liver. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with some drugs metabolized by the CYP450 system, such as theophylline (CYP1A2 substrate) given as a single oral dose. However, it may be prudent to monitor patients taking aminophylline or theophylline products and rabeprazole concurrently, since theophylline has a narrow therapeutic window.
    Thiazide diuretics: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Thiopental: Concurrent administration of rabeprazole with barbiturates may result in decreased rabeprazole plasma concentrations; monitor for signs and symptoms of reduced rabeprazole efficacy. Barbiturates induce CYP2C19 and rabeprazole is a CYP2C19 substrate.
    Tipranavir: Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Tipranavir markedly induces the hepatic cytochrome P-450 enzyme CYP2C19, an enzyme responsible for the metabolism of PPIs. However, since tipranavir is not given unless it is co-prescribed with ritonavir, a known marked enzyme inhibitor, a reduction in PPI metabolism may be unlikely to occur. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If tipranavir and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Tolterodine: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Torsemide: Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Trihexyphenidyl: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Trospium: The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Voriconazole: Rabeprazole is a substrate of CYP2C19. Voriconazole inhibits CYP2C19 and may cause a decrease in the metabolism of rabeprazole if coadministered.
    Warfarin: Omeprazole (CYP2C19 inhibitor) can prolong the elimination of warfarin, particularly R-warfarin which is partially metabolized by CYP2C19. The combined use of omeprazole and warfarin has been associated with reports of increased INR and prothrombin time (PT). In addition, post-marketing reports of the combination of esomeprazole and warfarin have indicated elevations in PT. There have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving other proton pump inhibitors (PPIs) (including esomeprazole, lansoprazole, rabeprazole, and pantoprazole and warfarin concomitantly. It is prudent to monitor the INR more closely if these agents are combined with warfarin.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies in pregnant women and no reports describing the use of rabeprazole during pregnancy in humans; changes in bone morphology have been observed in the offspring of animals treated with higher than human doses of a differnt PPI on a body surface area basis. The low molecular weight of rabeprazole (381) suggests that the drug will pass to the fetus. Human pregnancy experience with other PPIs (i.e., omeprazole and lansoprazole) have not shown a casual relationship with congenital malformations; however, there is a possibility that the true risk of malformation was missed due to study design and/or sample size. In the absence of sound exposure data, rabeprazole should be used during pregnancy only when clearly needed. If rabeprazole is required, it is best to avoid 1st trimester exposure. If inadvertent exposure does occur during the first 3 months of pregnancy, the known congenital risk for the fetus appears to be low. In 2009, a population-based observational cohort study explored a possible link between gastric acid suppressive therapy (e.g., proton pump inhibitors) during pregnancy and a diagnosis of allergic disease or a prescription for asthma or allergy medications in the exposed child. Among the cohort (n = 585,716), 1% of children exposed to gastric acid suppressive drugs in pregnancy received a diagnosis of allergic diease. For developing allergy or asthma, an increased OR of 1.43 and 1.51, respectively, were observed regardless of drug used, time of exposure during pregnancy, and maternal history of disease. Proposed possible mechanisms for a link include: (1) exposure to increased amounts of allergens could cause sensitization to digestion-labile antigens in the fetus; (2) the maternal Th2 cytokine pattern could promote an allergy prone phenotype in the fetus; (3) maternal allergen specific immunoglobulin could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Study limitations were present and confirmation of results are necessary before further conclusions can be drawn from this data. Risk versus benefit should be considered prior to use.

    It is not known whether rabeprazole is excreted into human breast milk. It is excreted into the milk of lactating rats; nursing pups exposed to rabeprazole had decreased weight gain after the drug was administered in late gestation and lactation. The clinical significance of this in humans is unknown. Since other PPIs are excreted in human milk, rabeprazole is expected to do so. Because of the potential for serious adverse reactions from rabeprazole in a breast-fed infant (including suppression of gastric acid secretion), a decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother's condition. Alternative therapies for consideration include antacids and H2 blockers.

    MECHANISM OF ACTION

    Mechanism of Action: Rabeprazole is a substituted benzimidazole proton-pump inhibitor that suppresses gastric acid secretion. It inhibits the gastric H+, K+ATPase enzyme pump at the secretory surface of the gastric parietal cell. This action is partially reversible; rabeprazole dissociates from the enzyme more readily than omeprazole. Rabeprazole is 2—10-fold more potent in vitro than omeprazole. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfonamide. A significant increase in gastric pH and decrease in basal acid output follow oral administration of rabeprazole. The median inhibitory effect of rabeprazole on 24 hour gastric acidity is 88% of maximal after the first dose. Rabeprazole 20 mg 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 exceeds 3.0 from 10% to 65%. Rabeprazole does not antagonize H2 or cholinergic receptors.
     
    Significant in vitro activity against Helicobacter pylori (H. Pylori) has been demonstrated. The minimum inhibitory concentrations (MICs) for rabeprazole are lower than those of omeprazole and lansoprazole. The clinical significance of this finding has not been established. Rabeprazole monotherapy increases the clearance rate of H. pylori; however, eradication does not occur without antimicrobial therapy.
     
    Similar to omeprazole and lansoprazole, hypergastrinemia can occur during rabeprazole therapy. Although prolonged hypergastrinemia has been associated with gastric tumors, long-term studies of proton pump inhibitors do not reveal development of tumors which was an initial concern in the animal models. Studies for up to one year showed that rabeprazole had no effect on the endocrine system.

    PHARMACOKINETICS

    Rabeprazole is administered orally. It is 96.3% bound to human plasma proteins. The plasma elimination half-life of rabeprazole ranges from 1 to 2 hours. Following a single oral dose of 14C-labeled rabeprazole, about 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 as metabolites. No unchanged rabeprazole was recovered in the urine or feces.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C19
    Rabeprazole is extensively metabolized by the liver, and has been shown in vitro to be a substrate of the CYP2C19 and CYP3A4 isoenzymes.. 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 primarily metabolism by CYP3A4 results in the sulphone metabolite, and further metabolism by 2C19 results in desmethyl rabeprazole. The thioether metabolite is formed by reduction of rabeprazole.  In vitro data only suggest that rabeprazole may inhibit the CYP2C19 and CYP3A4 isoenzymes. Rabeprazole was studied in a clinical trial in Japanese patients categorized as either poor or extensive metabolizers of the CYP2C19 genotype; gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. In theory, this could be due to higher rabeprazole plasma levels in poor metabolizers. It is unknown whether or not interactions of rabeprazole with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers.

    Oral Route

    AcipHex delayed-release tablets are enteric-coated to allow rabeprazole sodium, which is acid labile to pass through the stomach relatively intact. After oral administration of delayed-release tablets, peak plasma concentrations of rabeprazole occur over 2—5 hours and rabeprazole can be detected in plasma within 1 hour.The absolute bioavailability of rabeprazole is about 52%. Food delays the absorption, but does not affect the peak concentrations or bioavailability of rabeprazole.