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  • CLASSES

    Proton Pump Inhibitors/PPIs

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    An immediate-release product combining a proton pump inhibitor (PPI) and sodium bicarbonate buffer.
    Used for GERD, erosive esophagitis, gastric and duodenal ulcer, and stress ulcer prophylaxis in critically ill patients.
    Has an earlier detectable antisecretory effect that lasts at least as long as delayed-release omeprazole formulations.

    COMMON BRAND NAMES

    OmePPi, Zegerid

    HOW SUPPLIED

    OmePPi/Omeprazole, Sodium Bicarbonate/Zegerid Oral Cap: 20-1100mg, 40-1100mg
    Omeprazole, Sodium Bicarbonate/Zegerid Nasogastric Pwd F/Recon: 20-1680mg, 40-1680mg
    Omeprazole, Sodium Bicarbonate/Zegerid Oral Pwd F/Recon: 20-1680mg, 40-1680mg

    DOSAGE & INDICATIONS

    For the treatment of active duodenal ulcer.
    Oral dosage (powder for suspension or capsules)
    Adults

    20 mg PO once daily for up to 4 weeks. Some patients may require an additional 4 weeks of therapy.

    For the short-term treatment of active benign gastric ulcer.
    Oral dosage (powder for suspension or capsules)
    Adults

    40 mg PO once a day for 4—8 weeks. For endoscopically diagnosed gastric ulcer larger than 1 cm, 40 mg once daily was significantly more effective than 20 mg once daily at 8 weeks. For ulcer size 1 cm or less, no difference in healing rates between 40 mg and 20 mg daily doses were observed.

    For the treatment of gastroesophageal reflux disease (GERD).
    For symptomatic treatment of non-erosive GERD.
    Oral dosage (powder for suspension or capsules)
    Adults

    20 mg PO once daily given 60 minutes before first meal of the day, for up to 4 weeks. Most patients respond within 4 weeks. Some patients may require an additional 4 weeks of therapy. 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 increase to 20 mg PO twice daily or consider a 1-time switch to a different PPI. Refer nonresponders 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.

    For nocturnal acid breakthrough†.
    Oral dosage (powder for suspension)
    Adults

    40 mg once daily at bedtime or 20—40 mg PO twice daily (breakfast and bedtime). After repeated once-daily dosing of omeprazole; sodium bicarbonate 40 mg suspension or pantoprazole 40 mg delayed-release tablets, significantly fewer patients experienced nocturnal acid breakthrough (NAB) with omeprazole taken at bedtime than after pantoprazole taken before dinner (53% vs. 78%, respectively). Additionally, the percentages of patients with NAB after twice daily dosing of omeprazole 20 mg, omeprazole 40 mg, and pantoprazole 40 mg were 46.7%, 11.8%, and 70.6%, respectively.

    For the treatment of erosive esophagitis (erosive GERD).
    Oral dosage
    Adults

    20 mg PO once daily 60 minutes before first meal of the day, for 4 to 8 weeks. Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. For maintenance of healing, 20 mg PO once daily; periodically reassess need for continued PPI therapy. Controlled studies do not extend beyond 12 months.

    For stress gastritis prophylaxis in critically ill patients.
    Oral dosage (powder for suspension)
    Adults

    Initially, 40 mg PO, followed by 40 mg PO in 6—8 hours on day 1, then 40 mg PO once daily for up to 14 days. Use beyond 14 days has not been evaluated in critically ill patients. An evaluation comparing omeprazole; sodium bicarbonate oral suspension and IV cimetidine infusion for the prevention of upper GI bleeding found favorable results in the omeprazole-treated group. The 14-day study showed that omeprazole; sodium bicarbonate suspension administered via gastric tube, compared to IV cimetidine 50 mg/hour (after 300 mg IV loading dose), reduced the incidence of clinically significant bleeding (3.9% vs. 5.5%, respectively) and overt bleeding (19.1% vs. 32%, respectively). Additionally, inadequate pH control, defined as 2 consecutive gastric pH determinations of less than 4, were reported in 18% of omeprazole-treated patients compared to 58% of IV cimetidine-treated patients (p < 0.001).

    For the treatment of frequent pyrosis (heartburn).
    Oral dosage (Zegerid OTC capsules)
    Adults

    20 mg PO once daily for 14 days.

    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 given 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 one-third of all patients with esophageal eosinophilia on biopsy will respond to a PPI.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO (omeprazole 40 mg; 1100 mg sodium bicarbonate) for oral capsules and 40 mg/day PO (omeprazole 40 mg; 1680 mg sodium bicarbonate) for packets for oral suspension are recommended by the manufacturer; however, doses up to 80 mg/day have been studied for nocturnal acid breakthrough.

    Elderly

    40 mg/day PO (omeprazole 40 mg; 1100 mg sodium bicarbonate) for oral capsules and 40 mg/day PO (omeprazole 40 mg; 1680 mg sodium bicarbonate) for packets for oral suspension are recommended by the manufacturer; however, doses up to 80 mg/day have been studied for nocturnal acid breakthrough.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Consider dosage reduction in patients with hepatic impairment (see Contraindications/Precautions).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    Since omeprazole is highly protein bound, it is not likely to be significantly removed by hemodialysis. No dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer on an empty stomach, at least 60 minutes before meals. If given once daily, administer before the first meal of the day.

    Oral Solid Formulations

    Immediate-release capsules: Swallow intact capsule with water. Do not administer with any other liquid besides water. Do not open capsules and sprinkle the contents into food. The 20 mg and 40 mg capsules each contain 1100 mg sodium bicarbonate per capsule; two capsules of 20 mg are not equivalent to, and should not be substituted for, one 40 mg capsule.

    Oral Liquid Formulations

    Immediate-release oral suspension: Prepare the suspension by emptying packet contents into a small cup containing 1—2 tablespoons (15—30 ml) of water; do not use other liquids or foods. Stir the mixture well and administer immediately. Refill the cup with water and drink. The 20 mg and 40 mg suspension packets each contain 1680 mg sodium bicarbonate; two packets of 20 mg are not equivalent to, and should not be substituted for, one 40 mg packet.
    Patients with a gastric tube: Use the oral suspension. For patients receiving continuous gastric tube feeding, suspend the enteral feeding approximately 3 hours before and 1 hour after administration. For administration via nasogastric (NG) or orogastric (OG) tube, constitute the oral suspension with approximately 20 ml of water only, do not use other liquids or foods. Stir the mixture well and administer immediately, using an appropriately-sized syringe to instill the suspension into the tube, then flush the tube with an additional 20 ml of plain water.

    STORAGE

    OmePPi:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Zegerid:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the contraindications/precautions of omeprazole; sodium bicarbonate combination products. Clinicians may wish to consult the individual monographs for more information about each agent.

    Proton pump inhibitors (PPIs) hypersensitivity

    Omeprazole; sodium bicarbonate is contraindicated in patients with known hypersensitivity to omeprazole; sodium bicarbonate. Omeprazole is a proton pump inhibitor (PPI), and therefore should be used cautiously in patients with 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 (e.g., result in anaphylaxis, angioedema, or acute interstitial nephritis).

    Bartter's syndrome, corticosteroid therapy, Cushing's syndrome, hyperaldosteronism, hypocalcemia, hypokalemia, metabolic alkalosis, respiratory alkalosis

    The Zegerid brand of omeprazole; sodium bicarbonate contains 1680 mg (20 mEq) of sodium bicarbonate in each packet of oral suspension and 1100 mg (13 mEq) in each capsule. Because of the sodium bicarbonate content found in these formulations, the combination product should not be used in patients with metabolic alkalosis and hypocalcemia. Products containing sodium bicarbonate should be used cautiously in patients with Bartter's syndrome, hypokalemia, and respiratory alkalosis. Other causes of metabolic alkalosis include Cushing's syndrome and primary hyperaldosteronism; sodium bicarbonate should be used cautiously in patients with these conditions. Furthermore, milk-alkali syndrome may occur with the long-term coadministration of calcium or milk with bicarbonate. Sodium bicarbonate therapy should be used with caution in patients receiving corticotropin or corticosteroid therapy.

    Cardiac disease, heart failure, hypernatremia, hypertension, peripheral edema, pulmonary edema, renal disease, renal failure, renal impairment, sodium restriction

    The Zegerid brand of omeprazole; sodium bicarbonate contains 460 mg of sodium in each packet of oral suspension and 300 mg of sodium in each capsule. This additional sodium load should be taken into consideration when sodium restriction is required. Due to the sodium content, sodium bicarbonate products should be used with caution in patients with cardiac disease, heart failure, hypernatremia, renal impairment, renal disease, renal failure, peripheral edema, pulmonary edema, or other conditions in which sodium retention could be detrimental. Patients with hypertension should cautiously be prescribed sodium bicarbonate products; hypertension has been reported with the use of omeprazole; sodium bicarbonate in critically ill patients during clinical evaluation (see Adverse Reactions).

    Hepatic disease

    Omeprazole; sodium bicarbonate should be administered with caution to patients with hepatic disease since clearance of the drug can be prolonged. Dosage reduction should be considered in patients with hepatic impairment (e.g., cirrhotic liver disease), especially those receiving long-term therapy. In patients with chronic hepatic disease, the bioavailability of buffered omeprazole solution increases to approximately 100%, reflecting decreased first-pass effect. Additionally, the half-life increases to nearly 3 hours in chronic hepatic impairment as compared to the mean half-life of 1 hour in normal subjects. Plasma clearance averages 70 mL/min, compared to a value of 500—600 ml/min in normal subjects. In addition, omeprazole has been associated with hepatitis and, in rare instances, hepatic failure.

    Asian patients

    Asian patients exhibit a four-fold increase in AUC of omeprazole compared to Caucasian patients. The manufacturer of Zegerid states that dosage reduction should be considered when administering omeprazole; sodium bicarbonate to Asian patients, particularly when maintenance treatment for healing of erosive esophagitis is indicated. No specific dosage guidelines are available at this time.

    Gastric cancer

    Symptomatic response to therapy with omeprazole; sodium bicarbonate does not preclude the presence of gastric cancer or other malignancy. Omeprazole; sodium bicarbonate decreases intragastric acidity. Subsequently, the number of bacteria in gastric secretions and, correspondingly, the amount of carcinogenic N-nitroso compounds produced by these bacteria increase. The overall risk of carcinoid tumors during therapy with proton pump inhibitors (PPI) is low based on cumulative safety experience; monitoring of serum gastrin levels during PPI therapy is generally not necessary. One trial studied 25 patients with H2-receptor antagonist-resistant gastroesophageal reflux disease (GERD) who were treated and then followed on long-term (>= 4 years) omeprazole therapy; neoplasia or dysplasia were not seen in biopsies.

    Vitamin B12 deficiency

    Daily treatment with gastric acid-suppressing medication such as omeprazole over a long period of time (e.g., generally >= 2—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.

    Children, infants, neonates

    Safe and effective use of omeprazole; sodium bicarbonate has not been established in children. There are no adequate and well-controlled studies in neonates, infants, children and adolescents < 18 years with omeprazole; sodium bicarbonate (Zegerid) capsules or suspension.

    Pregnancy

    Omeprazole; sodium bicarbonate is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies on the use of omeprazole; sodium bicarbonate in pregnancy. Animal reproductive studies have been conducted with omeprazole and esomeprazole. Rats and rabbits dosed with esomeprazole up to 57 and 35 times, respectively, that of humans based on body surface area, showed no evidence of teratogenicity. However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses >= 33.6 times an oral human dose of 40 mg. Although animal studies are not always predictive of human effects, because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole use in pregnancy should be limited. In humans, omeprazole is known to cross the placenta to the fetus. Epidemiological evaluations have compared the rate of congenital abnormalities and stillbirths among infants exposed to omeprazole during pregnancy to similar findings for infants exposed to H2-receptor antagonists or other controls. Overall, slightly higher rates of congenital malformations (e.g., ventricular septal defects) and number of stillborn infants have been reported for cases where exposure to omeprazole occured in the first trimester of pregnancy and beyond. Although no untoward effects have been observed in humans, chronic use of sodium bicarbonate may lead to systemic alkalosis, and increased sodium intake can produce edema and weight increase. Use of omeprazole; sodium bicarbonate during pregnancy should be limited to cases where the benefit to the mother outweighs any potential risk to the fetus. If possible, avoid use in the first three months of pregnancy. 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

    According to the manufacturer, it is advisable to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Omeprazole is excreted into human breast milk and there is a potential for adverse reactions in the nursing infant, including suppression of gastric acid secretion. The manufacturer of omeprazole; sodium bicarbonate also states that sodium bicarbonate should be used use caution in breast-feeding mothers. Alternative therapies for consideration include antacids and H2 blockers. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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 omeprazole, 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.

    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).

    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 omeprazole; sodium bicarbonate. 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 (see Interactions) 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.

    Systemic lupus erythematosus (SLE)

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

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    pneumothorax / Early / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    bone fractures / Delayed / Incidence not known
    optic atrophy / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 1.5-4.5
    elevated hepatic enzymes / Delayed / 1.7-1.7
    hypernatremia / Delayed / 1.7-1.7
    stomatitis / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    edema / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    angina / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    metabolic alkalosis / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    tetany / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    blurred vision / Early / Incidence not known
    glycosuria / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    pyuria / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    headache / Early / 2.9-6.9
    abdominal pain / Early / 5.2-5.2
    nausea / Early / 4.0-4.0
    diarrhea / Early / 3.7-3.9
    vomiting / Early / 3.2-3.2
    flatulence / Early / 2.7-2.7
    infection / Delayed / 1.9-1.9
    rash (unspecified) / Early / 1.5-1.5
    dizziness / Early / 1.5-1.5
    asthenia / Delayed / 1.3-1.3
    cough / Delayed / 1.1-1.1
    back pain / Delayed / 1.1-1.1
    dysgeusia / Early / Incidence not known
    xerostomia / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    stool discoloration / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    leukocytosis / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    malaise / Early / Incidence not known
    petechiae / Delayed / Incidence not known
    xerosis / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    fever / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    fatigue / Early / Incidence not known
    vertigo / Early / Incidence not known
    tremor / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    drowsiness / Early / Incidence not known
    agitation / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    xerophthalmia / Early / Incidence not known
    ocular irritation / Rapid / Incidence not known
    gynecomastia / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    testicular pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with omeprazole 40 mg/day for 5 days. (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Acetaminophen: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Butalbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Urinary alkalinizing agents may increase the excretion of salicylates by increasing renal clearance. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected. (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Codeine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Dextromethorphan: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected. (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Diphenhydramine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Hydrocodone: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Oxycodone: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Pentazocine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Propoxyphene: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetaminophen; Pseudoephedrine: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected. (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Acetaminophen; Tramadol: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Acetazolamide: (Minor) Acetazolamide and sodium bicarbonate used concurrently increases the risk of renal calculus formation via calcium phosphate supersaturation.
    Acrivastine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Afatinib: (Major) If the concomitant use of omeprazole and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of omeprazole. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and omeprazole is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Alendronate: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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; Valsartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Alprazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as alprazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Amiloride: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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.
    Amitriptyline; Chlordiazepoxide: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Amlodipine; Atorvastatin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction. (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Amlodipine; Benazepril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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; Olmesartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Amlodipine; Telmisartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Amlodipine; Valsartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Ammonium Chloride: (Major) Citric acid; potassium citrate; sodium citrate and ammonium chloride should not be coadministered as they have opposing actions. It would be illogical to administer an acidifying agent (ammonium chloride) with a urinary alkalinizer (citric acid; potassium citrate; sodium citrate).
    Amobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Amphetamine: (Moderate) Proton pump inhibitors (PPIs) decrease the time to maximum concentration (Tmax) of amphetamine compared to when amphetamine is administered alone. If used together, monitor patients for clinical efficacy and adjust stimulant therapy based on clinical response. Some dosage forms of amphetamines should not be given with PPIs. Do not use Adzenys ER (amphetamine) extended-release oral suspension with gastric pH modulators, such as PPIs; concomitant use may result in dose-dumping by potentially changing the release profile of the extended-release suspension and increasing the exposure to amphetamine.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Proton pump inhibitors (PPIs) decrease the time to maximum concentration (Tmax) of amphetamine compared to when amphetamine is administered alone. If used together, monitor patients for clinical efficacy and adjust stimulant therapy based on clinical response. Some dosage forms of amphetamines should not be given with PPIs. Do not use Adzenys ER (amphetamine) extended-release oral suspension with gastric pH modulators, such as PPIs; concomitant use may result in dose-dumping by potentially changing the release profile of the extended-release suspension and increasing the exposure to amphetamine.
    Amphetamine; Dextroamphetamine: (Moderate) Proton pump inhibitors (PPIs) decrease the time to maximum concentration (Tmax) of amphetamine compared to when amphetamine is administered alone. If used together, monitor patients for clinical efficacy and adjust stimulant therapy based on clinical response. Some dosage forms of amphetamines should not be given with PPIs. Do not use Adzenys ER (amphetamine) extended-release oral suspension with gastric pH modulators, such as PPIs; concomitant use may result in dose-dumping by potentially changing the release profile of the extended-release suspension and increasing the exposure to amphetamine.
    Amphetamines: (Major) Concurrent use of amphetamines with urinary alkalinizing agents (e.g., sodium lactate, sodium acetate, potassium citrate, citric acid; sodium citrate, and tromethamine) should be avoided if possible. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged. The amphetamine dose should be adjusted accordingly if avoiding co-use is not possible. Monitor for high blood pressure, increased heart rate, nervousness, palpitations, insomnia, or changes in moods and behaviors.
    Ampicillin: (Major) 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: (Major) 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.
    Angiotensin II receptor antagonists: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Angiotensin-converting enzyme inhibitors: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Anticholinergics: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Minor) Use caution if omeprazole and aprepitant are used concurrently and monitor for an increase in omeprazole-related adverse effects for several days after administration of a multi-day aprepitant regimen. Omeprazole is a CYP3A4 substrate. 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 omeprazole. 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.
    Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as omeprazole during coadministration with armodafinil. A 40% increase in exposure of omeprazole was observed during coadministration with armodafinil. The clinical significance of this interaction is unknown.
    Ascorbic Acid, Vitamin C: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Aspirin, ASA: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as omeprazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as omeprazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Dipyridamole: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
    Atazanavir: (Severe) 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%. (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
    Atazanavir; Cobicistat: (Severe) 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%. (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while omeprazole is a CYP3A4 and P-gp substrate.
    Atenolol; Chlorthalidone: (Moderate) 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.
    Atorvastatin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction. (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
    Atorvastatin; Ezetimibe: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction. (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Atropine: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Avanafil: (Minor) Avanafil is a weak inhibitor of CYP2C19 isoenzymes. A single avanafil (200 mg) dose increased the AUC and Cmax of a single omeprazole (40 mg) dose, a CYP2C19 substrate, given once daily for 8 days by 5.9% and 8.6%, respectively.
    Axitinib: (Minor) Monitor patients for increased axitinib-related adverse events or altered axitinib efficacy if coadministration with omeprazole occurs. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Omeprazole is a CYP2C19 inhibitor and CYP1A2 inducer in vitro. Theoretically, exposure to axitinib may be affected. 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Azilsartan; Chlorthalidone: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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.
    Azithromycin: (Minor) Both omeprazole and azithromycin are P-glycoprotein (PGP) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together.
    Barbiturates: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Moderate) 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: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Minor) 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. (Minor) The concomitant use of bisacodyl tablets with antacids can cause the enteric coating of the bisacody tablet to dissolve prematurely, leading to possible gastric irritation or dyspepsia. Avoid antacids within 1 hour before or after the bisacodyl dosage.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Minor) Coadministration of bismuth subcitrate potassium and omeprazole resulted in a significant increase in the systemic absorption of bismuth. However, when administered in the FDA-approved dosage regimen, bismuth subcitrate potassium; metronidazole; tetracycline capsules (Pylera) is administered with omeprazole for 10 days. The manufacturer does not feel that short-term exposure to bismuth concentrations > 50 mcg/L will increase the risk of neurotoxicity; health care practitioners should be aware of this potential adverse effect.
    Bismuth Subsalicylate: (Moderate) Urinary alkalinizing agents may increase the excretion of salicylates by increasing renal clearance. (Minor) Coadministration of bismuth subcitrate potassium and omeprazole resulted in a significant increase in the systemic absorption of bismuth. However, when administered in the FDA-approved dosage regimen, bismuth subcitrate potassium; metronidazole; tetracycline capsules (Pylera) is administered with omeprazole for 10 days. The manufacturer does not feel that short-term exposure to bismuth concentrations > 50 mcg/L will increase the risk of neurotoxicity; health care practitioners should be aware of this potential adverse effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Urinary alkalinizing agents may increase the excretion of salicylates by increasing renal clearance. (Minor) Coadministration of bismuth subcitrate potassium and omeprazole resulted in a significant increase in the systemic absorption of bismuth. However, when administered in the FDA-approved dosage regimen, bismuth subcitrate potassium; metronidazole; tetracycline capsules (Pylera) is administered with omeprazole for 10 days. The manufacturer does not feel that short-term exposure to bismuth concentrations > 50 mcg/L will increase the risk of neurotoxicity; health care practitioners should be aware of this potential adverse effect.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) 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.
    Bisphosphonates: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering omeprazole with boceprevir due to an increased potential for omeprazole-related adverse events. If omeprazole 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 omeprazole. Omeprazole is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated omeprazole plasma concentrations.
    Bortezomib: (Minor) Bortezomib may inhibit CYP2C19 activity at therapeutic concentrations and increase exposure to drugs that are substrates for this enzyme including proton pump inhibitors.
    Bosentan: (Moderate) Monitor for decreased efficacy of omeprazole if coadministration with bosentan is necessary. Omeprazole is metabolized by CYP2C19 and CYP3A4. Bosentan is a moderate CYP3A4 inducer. The manufacturer of omeprazole recommends avoidance with strong inducers because decreased exposure of omeprazole can occur. Recommendations are not available for concomitant use with moderate inducers of CYP3A4.
    Bosutinib: (Major) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and proton-pump inhibitors, such as omeprazole, 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. (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and antacids may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and antacids by more than 2 hours.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Brompheniramine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Budesonide: (Major) Enteric-coated budesonide granules dissolve at a pH > 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and antacids, milk, or other 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. In general, it may be prudent to avoid drugs such as antacids in combination with enteric-coated budesonide. (Minor) 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: (Major) Enteric-coated budesonide granules dissolve at a pH > 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and antacids, milk, or other 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. In general, it may be prudent to avoid drugs such as antacids in combination with enteric-coated budesonide. (Minor) 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: (Moderate) 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: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Cabozantinib: (Moderate) Monitor for an increase in omeprazole-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of omeprazole may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and omeprazole is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Calcium Carbonate: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Calcium Carbonate; Magnesium Hydroxide: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Calcium Carbonate; Risedronate: (Major) 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. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Calcium Salts: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Calcium: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Calcium; Vitamin D: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Omeprazole is a PGP inhibitor/substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Omeprazole is a PGP inhibitor/substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control.
    Candesartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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.
    Capecitabine: (Moderate) Use caution if treatment with a proton pump inhibitor (PPI) is necessary in patients taking capecitabine, as progression-free survival (PFS) and overall survival (OS) may be adversely affected. The mechanism of this potential interaction is unknown and data are conflicting. In a posthoc, retrospective, subgroup analysis of a phase 3 clinical trial in patients with advanced or metastatic gastroesophageal cancer, administration of a PPI was associated with a significant decrease in PFS and OS in patients treated with capecitabine plus oxaliplatin (CapeOx) vs. patients who did not receive a PPI; a significant difference was not observed in the CapeOx plus lapatinib arm. Demographically, there were significantly more Asian patients in the PPI arm of this analysis; according to the manufacturer of capecitabine, Japanese patients have a 36% lower Cmax and 24% lower AUC for capecitabine compared with Caucasian patients. Additionally, there was not a significant increase in concentration dependent toxicities (e.g., hand-foot syndrome, rash, and diarrhea) or dose reductions in either arm. These observations are in line with a previous retrospective study in which patients with colorectal cancer receiving PPI treatment and adjuvant capecitabine also experienced poorer relapse-free survival compared with patients not receiving a PPI. Coadministration with antacids increased exposure to capecitabine and its metabolites, but this was not clinically significant or clinically relevant. Pharmacokinetic data on the impact of a PPI on capecitabine exposure are not available.
    Captopril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Moderate) Omeprazole may increase the Cmax, AUC, and elimination half-life of carbamazepine when given as an extended-release formulation. Monitor carbamazepine serum concentrations when omeprazole is added to the drug regimen.
    Carbetapentane; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Carbinoxamine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as omeprazole, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Carvedilol: (Moderate) Altered concentrations of omeprazole and/or carvedilol may occur during coadministration. Carvedilol and omeprazole are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Cefdinir: (Major) Antacids containing magnesium or aluminum can interfere with the absorption of cefdinir. If aluminum or magnesium containing antacids are required during cefdinir therapy, cefdinir should be taken at least 2 hours before or after the antacid.
    Cefditoren: (Major) Antacids containing magnesium or aluminum can interfere with the absorption of cefditoren. If aluminum or magnesium containing antacids are required during cefditoren therapy, cefditoren should be taken at least 2 hours before or after the antacid. Other orally administered aluminum salts and magnesium salts may also interfere with the absorption of cefditoren.
    Cefpodoxime: (Moderate) Because cefpodoxime proxetil requires a low gastric pH for dissolution, drugs which increase gastric pH, such as antacids, can decrease the bioavailability of cefpodoxime. (Moderate) 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: (Minor) 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: (Major) 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. (Moderate) Antacids can interfere with the oral absorption of cefuroxime axetil and may result in reduced antibiotic efficacy. If an antacid must be used while a patient is taking cefuroxime, administer the oral dosage of cefuroxime at least 1 hour before or 2 hours after the antacid.
    Ceritinib: (Moderate) Use caution if coadministration of ceritinib with omeprazole 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. (Moderate) Use caution if the concomitant use of ceritinib with sodium bicarbonate 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.
    Cetirizine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Chlordiazepoxide: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Chlordiazepoxide; Clidinium: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) 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.
    Chloroquine: (Major) Chloroquine absorption may be reduced by antacids. Administer chloroquine and antacids at least 4 hours apart.
    Chlorothiazide: (Moderate) 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.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Chlorpheniramine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Chlorpropamide: (Moderate) Urinary alkalinizing agents may increase the excretion of chlorpropamide by increasing renal clearance. Monitor for decreased efficacy of chlorpropamide (i.e., increased blood glucose) during coadministration.
    Chlorthalidone: (Moderate) 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: (Moderate) 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.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Urinary alkalinizing agents may increase the excretion of salicylates by increasing renal clearance.
    Chondroitin; Glucosamine: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm). (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Chromium: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Cilostazol: (Major) When significant CYP2C19 inhibitors, such as omeprazole, are administered concomitantly with cilostazol, the cilostazol dosage should be reduced by 50%. Cilostazol is metabolized by the CYP2C19 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP2C19. When given concurrently with omeprazole, cilostazol AUC is increased by 26% and the Cmax is increased by 18%; the AUC of the active metabolite 3,4-dehydro-cilostazol is increased by 69% and the Cmax is increased by 29%.
    Ciprofloxacin: (Moderate) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin when possible. A large proportion of ciprofloxacin is normally excreted unchanged in the urine. If sodium bicarbonate is used concomitantly, the solubility of ciprofloxacin might be decreased because of alkaline urine. Patients should be monitored for crystalluria, proper urination,and altered kidney function. Hydrate patients well to prevent the formation of highly concentrated urine. (Minor) Concomitant use of ciprofloxacin and omeprazole may decrease the AUC and Cmax of ciprofloxacin, but the clinical significance of this interaction is unknown. Codministration of a single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for 4 days resulted in a 16% reduction of mean Cmax and mean AUC of ciprofloxacin. A single 1000 mg oral dose of Cipro XR administered with omeprazole (40 mg once daily for 3 days) to 18 healthy volunteers resulted in a decrease in the ciprofloxacin mean AUC by 20% and Cmax by 23%. However, coadministration of a single 1000 mg oral dose of Proquin XR given 2 hours after the third dose of omeprazole (40 mg once daily for 3 days) to 27 healthy volunteers resulted in no changes in the ciprofloxacin AUC and Cmax. If ciprofloxacin is administered with omeprazole with magnesium, chelation of the ciprofloxacin would be expected; in general, it is recommended that ciprofloxacin be administered 2 hours before or 6 hours after any divalent cations like magnesium to help limit an interaction.
    Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with omeprazole, 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.
    Citric Acid; Potassium Citrate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Citric Acid; Potassium Citrate; Sodium Citrate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of omeprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and omeprazole is an inhibitor of CYP2C19. 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.
    Clomipramine: (Minor) Coadministration may result in increased clomipramine exposure. Omeprazole is a CYP2C19 inhibitor and clomipramine is a CYP2C19 substrate.
    Clonazepam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as clonazepam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Clopidogrel: (Major) Avoid concomitant use of clopidogrel and omeprazole as it significantly reduces 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, pantoprazole, lansoprazole, or dexlansoprazole. 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.
    Clorazepate: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as clorazepate. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Clozapine: (Moderate) The addition of omeprazole to clozapine therapy resulted in a roughly 40% reduction in clozapine plasma concentrations in at least 2 patients. Omeprazole is an inducer of CYP1A2, one of the isoenzymes reponsible for the metabolism of clozapine. According to the manufacturer of clozapine, patients receiving clozapine in combination with a weak to moderate CYP1A2 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary. If the inducer is discontinued, monitor for adverse reactions, and consider reducing the clozapine dose if necessary.
    Cobicistat: (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while omeprazole is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Separate administration of elvitegravir and antacids by at least 2 hours. Due to the formation of ionic complexes in the gastrointestinal tract, simultaneous administration results in lower elvitegravir plasma concentrations. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while omeprazole is a CYP3A4 and P-gp substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as omeprazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Separate administration of elvitegravir and antacids by at least 2 hours. Due to the formation of ionic complexes in the gastrointestinal tract, simultaneous administration results in lower elvitegravir plasma concentrations. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while omeprazole is a CYP3A4 and P-gp substrate.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and omeprazole is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and omeprazole is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Colchicine: (Moderate) The action of colchicine is potentiated by alkalinizing agents. The colchicine dose may need adjustment.
    Collagenase: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Conivaptan: (Moderate) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and omeprazole, a CYP3A4/P-gp substrate. Concurrent use may result in elevated omeprazole serum concentrations. According to the manufacturer of conivaptan, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as omeprazole, should be avoided. Coadministration of conivaptan with other CYP3A substrates (midazolam, simvastatin, amlodipine) has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with omeprazole. Treatment with omeprazole may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Cranberry, Vaccinium macrocarpon Ait.: (Minor) Because antacids can alkalinize the urine, they can interact with urinary acidifiers, such as ascorbic acid. Frequent use of high doses of antacids should be avoided by patients receiving urinary acidifiers.
    Cyanocobalamin, Vitamin B12: (Moderate) 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. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Cysteamine: (Major) In general, cysteamine may be administered with electrolyte and mineral replacements necessary for managing Fanconi syndrome, as well as with vitamin D and thyroid hormone. However, delayed-release cysteamine (Procysbi) should be administered at least 1 hour before or 1 after medications that increase gastric pH, including those containing bicarbonate or carbonate (i.e., sodium bicarbonate). Drugs that increase the gastric pH, such as bicarbonate and carbonate, may cause the premature release of cysteamine from delayed-release capsules, leading to an increase in WBC cystine concentration. (Major) 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.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with omeprazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing omeprazole including omeprazole; sodium bicarbonate. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like omeprazole in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with omeprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) The concomitant use of dabrafenib and omeprazole may lead to decreased omeprazole concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of omeprazole efficacy. In vitro, dabrafenib is an inducer of CYP2C isoenzymes via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Omeprazole is a sensitive CYP2C19 substrate. (Moderate) Space the administration of antacids from dabrafenib by at least 2 hours. Antacids elevate the gastric pH and may alter the solubility of dabrafenib. Therefore, the concomitant use of dabrafenib and antacids 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.
    Daclatasvir: (Minor) Systemic exposure of omeprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of omeprazole; monitor patients for potential adverse effects.
    Darifenacin: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day.
    Darunavir; Cobicistat: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while omeprazole is a CYP3A4 and P-gp substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. (Moderate) Dosage adjustments of omeprazole may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in decreased omeprazole serum concentrations. Monitor for decreasing efficacy and consider increasing the omeprazole dose if needed; however, adult doses should be limited to no more than 40 mg/day. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. (Moderate) Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dasatinib: (Major) 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. (Major) The solubility of dasatinib is pH dependent. Simultaneous administration of dasatinib and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dasatinib dose.
    Delavirdine: (Major) 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. (Major) Coadministration of delavirdine with antacids results in decreased absorption of delavirdine. Administration of delavirdine and antacids should be separated by at least 1 hour.
    Desiccated Thyroid: (Major) Antacids have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Administer thyroid hormones at least 4 hours before or after antacids.
    Desloratadine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Dexamethasone: (Moderate) Monitor for decreased efficacy of omeprazole if coadministration with dexamethasone is necessary. Omeprazole is metabolized by CYP2C19 and CYP3A4. Dexamethasone is a moderate CYP3A4 inducer. The manufacturer of omeprazole recommends avoidance with strong inducers because decreased exposure of omeprazole can occur. Recommendations are not available for concomitant use with moderate inducers of CYP3A4.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Dexmethylphenidate: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release dexmethylphenidate (Focalin XR) have not been studied. Per the manufacturer of extended-release dexmethylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release dexmethylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release dexmethylphenidate. (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release dexmethylphenidate (Focalin XR) have not been studied. Per the manufacturer of extended-release dexmethylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of sodium bicarbonate or other acid suppressants could alter the release of extended-release dexmethylphenidate, resulting in reduced or increased absorption. Patients receiving sodium bicarbonate should be monitored for adverse effects and reduced therapeutic efficacy of extended-release dexmethylphenidate.
    Dextroamphetamine: (Moderate) Proton pump inhibitors (PPIs) decrease the time to maximum concentration (Tmax) of amphetamine compared to when amphetamine is administered alone. If used together, monitor patients for clinical efficacy and adjust stimulant therapy based on clinical response. Some dosage forms of amphetamines should not be given with PPIs. Do not use Adzenys ER (amphetamine) extended-release oral suspension with gastric pH modulators, such as PPIs; concomitant use may result in dose-dumping by potentially changing the release profile of the extended-release suspension and increasing the exposure to amphetamine.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Dextromethorphan; Quinidine: (Major) Urinary alkalinization increases the renal tubular reabsorption of quinidine, resulting in higher quinidine serum concentrations which may lead to toxicity. Avoid citric acid; potassium citrate; sodium citrate administration to any patient receiving treatment with quinidine.
    Diazepam: (Moderate) Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole can increase the plasma concentrations and the elimination half-life of diazepam. It is recommended that patients receiving omeprazole and diazepam concomitantly should be monitored for enhanced diazepam response. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
    Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as omeprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as omeprazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Dicyclomine: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Diflunisal: (Moderate) Concurrent use of diflunisal with antacids, such as sodium bicarbonate, may reduce plasma diflunisal concentrations. The effect may be clinically significant if antacids are used on a continuous schedule.
    Digoxin: (Moderate) Omeprazole 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. Omeprazole increases the AUC of digoxin by about 10%. 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. Because, 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Diphenhydramine; Naproxen: (Minor) Concomitant administration of antacids can delay the absorption of naproxen. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours.
    Dirithromycin: (Minor) Antacids can interfere with the absorption of dirithromycin. If antacids must be used while a patient is taking these antibiotics, separate the administration by at least 2 hours.
    Disulfiram: (Minor) In one patient, the combined use of disulfiram and omeprazole caused disorientation, confusion, and nightmares. These reactions occurred on two separate challenges when omeprazole was added to disulfiram therapy. Caution is advised when using disulfiram and omeprazole together.
    Donepezil; Memantine: (Moderate) Urinary alkalinizing agents may decrease the elimination of memantine, resulting in drug accumulation and potential toxicity. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Memantine should be used with caution with drugs known to increase urinary pH.
    Doxepin: (Moderate) Doxepin is primarily metabolized by CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9. Omeprazole inhibits the CYP2C19 isoenzyme in vitro and in vivo and the CYP2C9 isoenzyme in vitro. In vitro, omeprazole induces the CYP1A2 isoenzyme. The clinical significance of this potential interaction is not known; monitor patients receiving doxepin and omeprazole concurrently for both doxepin efficacy and potential adverse effects.
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as omeprazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Doxorubicin: (Moderate) Omeprazole is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of omeprazole and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with omeprazole is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; omeprazole is a moderate inhibitor of CYP2C9 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Omeprazole 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.
    Edoxaban: (Moderate) Coadministration of edoxaban and omeprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and omeprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of omeprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C9 or CYP2C19.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as omeprazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C9 or CYP2C19.
    Eliglustat: (Minor) Coadministration of omeprazole and eliglustat may result in increased plasma concentrations of omeprazole. Monitor patients closely for omeprazole-related adverse effects; if appropriate, consider reducing the omeprazole dosage and titrating to clinical effect. Omeprazole is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Eltrombopag: (Major) Eltrombopag chelates polyvalent cations (e.g., antacids) in food, mineral supplements, and antacids. In a clinical study, systemic exposure to eltrombopag was decreased by 70% when it was administered with a polyvalent cation-containing antacid. Administer eltrombopag at least 2 hours before or 4 hours after any oral products containing polyvalent cations, such as magaldrate. (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as omeprazole, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered.
    Elvitegravir: (Moderate) Separate administration of elvitegravir and antacids by at least 2 hours. Due to the formation of ionic complexes in the gastrointestinal tract, simultaneous administration results in lower elvitegravir plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Severe) 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. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Severe) 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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as omeprazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as omeprazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enalapril, Enalaprilat: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Enalapril; Felodipine: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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.
    Enzalutamide: (Major) Avoid concomitant use of enzalutamide, a strong CYP3A4 inducer and a moderate CYP2C19 inducer, and omeprazole, a CYP3A4 and CYP2C19 substrate, as omeprazole plasma exposure may be reduced. In a drug interaction trial in patients with castration-resistant prostate cancer, the AUC and Cmax of omeprazole was decreased following a single oral dose of omeprazole 20 mg administered after at least 55 days of oral enzalutamide 160 mg/day.
    Ephedrine: (Moderate) Sodium bicarbonate-induced urinary alkalization can increase the half-life of ephedrine.
    Eprosartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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: (Major) Avoid the coadministration of erlotinib with omeprazole if possible, as there are multiple issues with concomitant use. Erlotinib solubility is pH dependent, and solubility decreases as pH increase; increasing the dose may not compensate for this loss of exposure. Additionally, erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Omeprazole is a CYP1A2 inducer in vitro. The manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals to a maximum of 300 mg when used with CYP1A2 inducers; however, this may not be effective due to the solubility issue. Omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively. In addition to the pharmacokinetic interaction, In a single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) decreased the AUC of erlotinib by 64% (95% CI, 46% to 76%) in current smokers compared with former/never smokers. Steady-state trough concentrations of erlotinib were approximately 2-fold less in current smokers compared with former/never smokers in a separate study of patients with NSCLC. Coadministration with omeprazole may also decrease erlotinib exposure. (Major) 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 may decrease the absorption of erlotinib. No formal analysis has been performed to assess the impact of antacids on erlotinib pharmacokinetics; however, if coadministration is necessary, the manufacturer recommends separation of antacids and erlotinib by several hours.
    Escitalopram: (Moderate) The plasma concentration of escitalopram, a CYP2C19 substrate, may be increased when administered concurrently with omeprazole, a CYP2C19 inhibitor. If these drugs are used together, monitor for escitalopram-associated adverse reactions.
    Eslicarbazepine: (Moderate) Eslicarbazepine may inhibit the CYP2C19-mediated and induce the CYP3A4-mediated metabolism of omeprazole; 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.
    Esomeprazole; Naproxen: (Minor) Concomitant administration of antacids can delay the absorption of naproxen. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours.
    Estazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as estazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Ethacrynic Acid: (Moderate) 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.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Antacids may decrease the absorption of oral iron preparations. At higher pH values, iron is more readily ionized to its ferric state and is more poorly absorbed. Doses of antacids and iron should be taken as far apart as possible to minimize the potential for interaction.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Antacids may decrease the absorption of oral iron preparations. At higher pH values, iron is more readily ionized to its ferric state and is more poorly absorbed. Doses of antacids and iron should be taken as far apart as possible to minimize the potential for interaction.
    Ethotoin: (Major) The oral absorption of ethotoin may be reduced by antacids. Separating the administration of ethotoin and antacids by at least 2 hours will help minimize the possibility of interaction.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with omeprazole. Omeprazole is an inhibitor of P-glycoprotein (P-gp) and etoposide, VP-16 is a P-gp substrate. Coadministration may increase etoposide concentrations.
    Ezetimibe: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Ezetimibe; Simvastatin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction. (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, 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 omeprazole during coadministration with fenofibric acid.
    Fesoterodine: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Fexofenadine: (Major) Co-administration with antacids within 15 minutes decreases the AUC and Cmax of fexofenadine. Separate administration is recommended.
    Fexofenadine; Pseudoephedrine: (Major) Co-administration with antacids within 15 minutes decreases the AUC and Cmax of fexofenadine. Separate administration is recommended. (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Flavoxate: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Flecainide: (Moderate) Urinary alkalinization can decrease the renal clearance of flecainide, resulting in an increased elimination half-life and AUC for flecainide.
    Flibanserin: (Major) 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.
    Flurazepam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as flurazepam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Fluvastatin: (Moderate) Concomitant administration of omeprazole with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%.
    Fluvoxamine: (Moderate) Omeprazole is a primary substrate of CYP2C19 and CYP3A4. Reduced metabolism and resulting elevated plasma concentrations of omeprazole may occur if combined with fluvoxamine. Fluvoxamine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4. Concomitant administration of omeprazole and a combined inhibitor of CYP2C19 and CYP3A4 resulted in more than doubling of the omeprazole exposure. No specific dose adjustments are recommended, unless the patient is receiving high doses of omeprazole, as for Zollinger-Ellison Syndrome; in such patients, omeprazole dose reduction might be necessary.
    Food: (Moderate) Food or medicines containing a high sodium content (e.g., tomato juice) could increase the risk of complications of sodium excess when given with sodium bicarbonate. Patients and clinicians should be aware of the amount of sodium intake in medications and foods.
    Fosamprenavir: (Moderate) The administration of an aluminum hydroxide and magnesium hydroxide containing antacid with fosamprenavir decreased fosamprenavir Cmax and AUC. It is recommended that the administration of fosamprenavir and antacids be separated by at least 1 hour.
    Fosinopril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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.
    Fosphenytoin: (Moderate) Omeprazole can exhibit a dose-dependent inhibition of the hepatic cytochrome P-450 enzyme system, specifically CYP2C19. Because of this, omeprazole can interfere with the clearance of drugs metabolized via this pathway, such as phenytoin or fosphenytoin, resulting in increased phenytoin plasma concentrations. Clinical data do not exist, but an interaction is possible based on the known pathways of elimination. Patients should be monitored carefully for signs of increased drug effect if omeprazole is used with these drugs. In addition, 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.
    Furosemide: (Moderate) 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.
    Gabapentin: (Major) Antacids have been shown to reduce the oral bioavailability of gabapentin by roughly 20%. This decrease in bioavailability was about 5% when gabapentin was administered 2 hours after the antacid. It is recommended that gabapentin be taken at least 2 hours following the administration of antacids in order to avoid a significant interaction.
    Gastrointestinal Enzymes: (Major) The effectiveness of gastrointestinal enzymes can be diminished with concurrent administration of antacids. In-vitro studies suggest that calcium and magnesum cations exert their deleterious effect on replacement enzyme therapy by formation of poorly soluble calcium or magnesium soaps and precipitation of glycine conjugated bile salts.
    Gefitinib: (Moderate) If possible, avoid the concomitant use of gefitinib with antacids. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of antacid. 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%. (Moderate) If possible, avoid the concomitant use of gefitinib with omeprazole. If coadministration is necessary, give gefitinib 12 hours after the last dose or 12 hours before the next dose of omeprazole. 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%.
    Glipizide: (Moderate) Antacids have been reported to increase the absorption of glipizide, enhancing their hypoglycemic effects. Although the exact mechanism is not known, theoretically it may be due to alterations in gastric pH. Consider closely monitoring blood glucose concentrations.
    Glipizide; Metformin: (Moderate) Antacids have been reported to increase the absorption of glipizide, enhancing their hypoglycemic effects. Although the exact mechanism is not known, theoretically it may be due to alterations in gastric pH. Consider closely monitoring blood glucose concentrations.
    Glucosamine: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Glyburide: (Moderate) Antacids have been reported to increase the absorption of non-micronized glyburide, enhancing their hypoglycemic effects. Although the exact mechanism is not known, theoretically it may be due to alterations in gastric pH. Consider closely monitoring blood glucose concentrations.
    Glyburide; Metformin: (Moderate) Antacids have been reported to increase the absorption of non-micronized glyburide, enhancing their hypoglycemic effects. Although the exact mechanism is not known, theoretically it may be due to alterations in gastric pH. Consider closely monitoring blood glucose concentrations.
    Glycopyrrolate: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Guaifenesin; Potassium Guaiacolsulfonate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Guaifenesin; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Halofantrine: (Major) The oral absorption of halofantrine may be hindered by the concomitant use of antacids, and perhaps other antacids. Stagger the administration of halofantrine and antacids by at least 2 hours to limit an interaction.
    Hetastarch; Dextrose; Electrolytes: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm). (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Homatropine; Hydrocodone: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) 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: (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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: (Moderate) 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: (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. (Moderate) 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: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients. (Moderate) 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.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm). (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Hydrocodone; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Hydroxychloroquine: (Major) Hydroxychloroquine absorption may be reduced by antacids as has been observed with the structurally similar chloroquine. Administer hydroxychloroquine and antacids at least 4 hours apart. Of note, a study demonstrated no significant difference in hydroxychloroquine serum concentration in patients taking concomitant antacids (n = 14) compared to those not taking antacids (n = 495).
    Hyoscyamine: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Ibritumomab Tiuxetan: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Ibuprofen; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with omeprazole, a CYP3A substrate, as omeprazole toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Indacaterol; Glycopyrrolate: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Indinavir: (Major) Omeprazole has been reported to decrease the oral bioavailability of indinavir. In one study, indinavir plasma levels fell to below 95% of normal in roughly half of the patients receiving omeprazole concurrently. An increase in indinavir dosage resolved the interaction. It is unclear if other gastric acid-pump inhibitors would interact with indinavir in this manner.
    Indomethacin: (Moderate) Antacids may inhibit the oral absorption of indomethacin. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
    Iodine; Potassium Iodide, KI: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Irbesartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Iron Salts: (Major) Antacids may decrease the absorption of oral iron preparations. At higher pH values, iron is more readily ionized to its ferric state and is more poorly absorbed. Doses of antacids and iron should be taken as far apart as possible to minimize the potential for interaction. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Iron: (Major) Antacids may decrease the absorption of oral iron preparations. At higher pH values, iron is more readily ionized to its ferric state and is more poorly absorbed. Doses of antacids and iron should be taken as far apart as possible to minimize the potential for interaction. (Major) 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: (Moderate) Concomitant use of isavuconazonium with omeprazole may result in increased serum concentrations of omeprazole. Omeprazole is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Antacids, especially those containing aluminum salts, decrease the absorption of INH, possibly by a reduction in gastric emptying caused by aluminum. Administration of INH 1 hour before antacids is recommended.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Antacids, especially those containing aluminum salts, decrease the absorption of INH, possibly by a reduction in gastric emptying caused by aluminum. Administration of INH 1 hour before antacids is recommended. (Major) 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. (Moderate) Concomitant use of sodium bicarbonate and rifampin may decrease the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of sodium bicarbonate.
    Isoniazid, INH; Rifampin: (Major) Antacids, especially those containing aluminum salts, decrease the absorption of INH, possibly by a reduction in gastric emptying caused by aluminum. Administration of INH 1 hour before antacids is recommended. (Major) 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. (Moderate) Concomitant use of sodium bicarbonate and rifampin may decrease the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of sodium bicarbonate.
    Itraconazole: (Moderate) Administer antacids at least 2 hours before or 2 hours after oral itraconazole to minimize the potential for an interaction. Because itraconazole oral bioavailability requires an acidic environment for solubility, its absorption may be decreased with concomitant administration of antacids. (Moderate) Administer proton pump inhibitors at least 2 hours before or 2 hours after oral itraconazole to minimize the potential for an interaction. Because itraconazole oral bioavailability requires an acidic environment for solubility, its absorption may be decreased with concomitant administration of proton pump inhibitors.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and omeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketoconazole: (Major) Because ketoconazole requires an acidic pH for absorption, coadministration of a proton pump inhibitor (PPI) with ketoconazole can cause a notable decrease in the bioavailability of ketoconazole. PPIs 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. (Major) 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; ketoconazole should be administered at least 2 hours before or 1 hour after antacids. 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.
    Lactulose: (Minor) Oral, nonabsorbable antacids may interfere with the decrease in colon pH necessary for lactulose's action.
    Lansoprazole; Naproxen: (Minor) Concomitant administration of antacids can delay the absorption of naproxen. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours.
    Ledipasvir; Sofosbuvir: (Major) 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. (Moderate) Separate administration of ledipasvir and antacids by at least 4 hours. Solubility of ledipasvir decreases as gastric pH increases; thus, simultaneous administration of these drugs may result in lower ledipasvir plasma concentrations.
    Lesinurad: (Moderate) Use lesinurad and omeprazole together with caution; omeprazole may increase the systemic exposure of lesinurad. Omeprazole is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and omeprazole together with caution; omeprazole may increase the systemic exposure of lesinurad. Omeprazole is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Levothyroxine: (Major) Antacids have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Administer thyroid hormones at least 4 hours before or after antacids.
    Liothyronine: (Major) Antacids have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Administer thyroid hormones at least 4 hours before or after antacids.
    Liotrix: (Major) Antacids have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Administer thyroid hormones at least 4 hours before or after antacids.
    Lisinopril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Lithium: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with lithium, especially patients who are stabilized on lithium, as urinary alkalinization increases the renal clearance of lithium. If coadministration can not be avoided, monitor lithium serum concentrations and patient clinical response very closely. Also of note, lithium clearance is increased if hypernatremia occurs.
    Loop diuretics: (Moderate) 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.
    Loperamide: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with omeprazole, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with omeprazole, a P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. (Moderate) Use caution when administering lopinavir; ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while lopinavir is a P-gp inhibitor. Coadministration of lopinavir; ritonavir with CYP3A and P-gp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined. (Moderate) Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Loratadine; Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Losartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Lovastatin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Lovastatin; Niacin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Luliconazole: (Minor) Theoretically, luliconazole may increase the side effects of omeprazole, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of omeprazole. 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: (Minor) Use caution when administering ivacaftor and omeprazole concurrently. Ivacaftor is an inhibitor of CYP3A and P-glycoprotein (Pgp). Co-administration of ivacaftor with CYP3A and Pgp substrates, such as omeprazole, can increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of omeprazole by substantially decreasing its systemic exposure. If used together, an omeprazole dosage adjustment may be necessary to obtain the desired therapeutic effect. Omeprazole is a CYP3A4 and CYP2C19 substrate; it is also a substrate and inhibitor of the P-glycoprotein (P-gp) transport system. Lumacaftor; ivacaftor is a strong inducer of CYP3A; in vitro data suggests is also has the potential to induce CYP2C19 and both induce and inhibit P-gp.
    Magnesium Salicylate: (Moderate) Urinary alkalinizing agents may increase the excretion of salicylates by increasing renal clearance.
    Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects with the coadministration of maraviroc and omeprazole as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp); omeprazole is an inhibitor of P-gp. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
    Mefenamic Acid: (Moderate) Ingestion of mefenamic acid with antacids is not recommended. Administration with an antacid containing 1.7 grams of magnesium hydroxide resulted in a 36 percent increase in the area under the time versus concentration curve of mefenamic acid.
    Mefloquine: (Moderate) Antacids 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. (Moderate) 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.
    Memantine: (Moderate) Urinary alkalinizing agents may decrease the elimination of memantine, resulting in drug accumulation and potential toxicity. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Memantine should be used with caution with drugs known to increase urinary pH.
    Mepenzolate: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Mesalamine, 5-ASA: (Major) Do not coadminister mesalamine extended-release capsules (Apriso) with antacids. Apriso is a pH-dependent, delayed-release product with an enteric coating that dissolves at a pH of at least 6. Theoretically, the delayed-release tablets, Lialda, may interact with drugs that raise the gastric pH. The delayed-release tablets have a gastroresistant film that covers the mesalamine tablet core; the film covering delays the initial release of the 5-ASA until the tablet is exposed to a pH of at least 7. (Major) 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: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.
    Methenamine; Sodium Acid Phosphate: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid the administration of Alkalinizing agents to patients who are being treated with methenamine, as an acidic urine is required for methenamine therapeutic efficacy. Alkalinized urine decreases methenamine efficacy by increasing the amount of non-ionized drug available for renal tubular reabsorption and inhibits the conversion of methenamine to formaldehyde, which is the active bacteriostatic form. (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Methotrexate: (Major) Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitors (PPIs); a temporary withdrawal of the PPI should be considered in some patients receiving high-dose methotrexate. 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) 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: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate. (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Metolazone: (Moderate) 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.
    Mexiletine: (Major) If alkalinizing agents, such as sodium bicarbonate, are administered concomitantly with mexiletine, urinary excretion and plasma half-life of the antiarrhythmic can be altered. Elimination of mexiletine is decreased when the urine is alkaline and increased when it is acidic. Dosage adjustments should be made as necessary.
    Midazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as midazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Mitotane: (Moderate) Use caution if mitotane and omeprazole are used concomitantly, and monitor for decreased efficacy of omeprazole and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and omeprazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of omeprazole.
    Modafinil: (Minor) 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.
    Moexipril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Montelukast: (Moderate) Caution is advised when administering montelukast with CYP2C9 inhibitors such as omeprazole. In vitro studies using human liver microsomes indicate that CYP2C9 is involved in the metabolism of montelukast. In theory, it is possible that potent CYP2C9 inhibitors would reduce the clearance of montelukast.
    Mycophenolate: (Major) Coadministration of mycophenolate mofetil with antacids decreases the bioavailability of mycophenolate mofetil. Aluminum or magnesium hydroxide antacids decrease AUC of mycophenolic acid by about 17%. Avoid administration of mycophenolate mofetil with agents that may decrease its absorption. (Moderate) 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).
    Naproxen: (Minor) Concomitant administration of antacids can delay the absorption of naproxen. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours.
    Naproxen; Pseudoephedrine: (Minor) Concomitant administration of antacids can delay the absorption of naproxen. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours. (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Naproxen; Sumatriptan: (Minor) Concomitant administration of antacids can delay the absorption of naproxen. Periodic antacid use should not be problematic as long as the antacid and enteric-coated naproxen administration are separated by at least 2 hours.
    Nebivolol; Valsartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Nelfinavir: (Major) 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.
    Neratinib: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased efficacy of neratinib. Concomitant use with lansoprazole decreased neratinib exposure by 65%. Concomitant use with other pH lowering agents was not studied, but a decrease in the AUC of neratinib is considered likely. (Moderate) Administer neratinib at least 3 hours after administration of sodium bicarbonate if concomitant use is necessary due to the risk of decreased efficacy of neratinib. Sodium bicarbonate is an antacid. Concomitant use with a proton pump inhibitor decreased neratinib exposure by 65%. Concomitant use with other pH lowering agents was not studied, but a decrease in the AUC of neratinib is considered likely.
    Niacin; Simvastatin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Nilotinib: (Major) 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. (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Nintedanib: (Moderate) Omeprazole is a moderate inhibitor of P-glycoprotein (P-gp) and nintedanib is a P-gp substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of omeprazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nitrofurantoin: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Norfloxacin: (Moderate) Crystalluria related to norfloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving norfloxacin when possible. A large proportion of norfloxacin is normally excreted unchanged in the urine. If sodium bicarbonate is used concomitantly, the solubility of norfloxacin might be decreased because of alkaline urine. Patients should be monitored for crystalluria, proper urination, and altered kidney function. Hydrate patients well to prevent the formation of highly concentrated urine.
    Obeticholic Acid: (Minor) Concurrent administration of 20 mg omeprazole as a single dose with obeticholic acid 10 mg once daily resulted in a 32% increase in omeprazole AUC and a 33% increase in omeprazole Cmax. The clinical significance of this interaction is unknown. Even though omeprazole is a CYPC19 substrate, obeticholic acid is not expected to inhibit the CYPC19 isoenzyme. The mechanism of this interaction has not been described.
    Octreotide: (Minor) 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.
    Olmesartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. (Moderate) Dosage adjustments of omeprazole may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in decreased omeprazole serum concentrations. Monitor for decreasing efficacy and consider increasing the omeprazole dose if needed; however, adult doses should be limited to no more than 40 mg/day. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. (Moderate) Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Oritavancin: (Moderate) Administration of oritavancin, a weak inhibitor of CYP2C19, with omeprazole resulted in a 15% increase in the ratio of omeprazole to 5-OH-omeprazole concentrations in the plasma. Monitor patients for omeprazole toxicities, such as headache or gastrointestinal distress, if these drugs are administered concurrently.
    Oxcarbazepine: (Minor) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Pancrelipase: (Major) The effectiveness of gastrointestinal enzymes can be diminished with concurrent administration of antacids. In-vitro studies suggest that calcium and magnesum cations exert their deleterious effect on replacement enzyme therapy by formation of poorly soluble calcium or magnesium soaps and precipitation of glycine conjugated bile salts.
    Pantothenic Acid, Vitamin B5: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Pazopanib: (Major) 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. (Moderate) Pazopanib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of pazopanib and antacids that elevate the gastric pH may reduce the bioavailability of pazopanib. If coadministration of pazopanib and a short-acting antacid is necessary, separate the dosing by several hours.
    Penicillamine: (Moderate) Because penicillamine chelates heavy metals, it is possible that antacids could reduce penicillamine bioavailability, which can decrease the therapeutic effects of penicillamine. Simultaneous administration should be avoided; separate dosing by at least 2 hours to limit an interaction.
    Pentobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Perindopril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Perindopril; Amlodipine: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Phenobarbital: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Phenytoin: (Moderate) Because the absorption of phenytoin suspension can be reduced by antacids containing magnesium, aluminum, or calcium, administration at the same time of day should be avoided when possible. Ingestion times of phenytoin capsules and calcium antacids should be staggered in patients with low serum phenytoin levels to prevent absorption difficulties. Studies evaluating the effects of magnesium-aluminium antacids on the absorption of phenytoin capsules or tablets have yielded conflicting results. Nevertheless, serum phenytoin levels and clinical response should be closely monitored if these agents are co-administered. The mechanisms by which antacids reduce phenytoin absorption may involve increased gastric transit time, chelation, adsorption, and/or altered solubility. The oral absorption of phenytoin may be reduced by calcium carbonate (e.g., as found in antacids) or other calcium salts. Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of the interaction is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic phenytoin concentrations. Separating the administration of phenytoin and antacids or calcium salts by at least 2 hours will help minimize the possibility of interaction. (Moderate) Omeprazole can exhibit a dose-dependent inhibition of the hepatic cytochrome P-450 enzyme system, specifically CYP2C19. Because of this, omeprazole can interfere with the clearance of drugs metabolized via this pathway, such as phenytoin or fosphenytoin, resulting in increased phenytoin plasma concentrations. Clinical data do not exist, but an interaction is possible based on the known pathways of elimination. Patients should be monitored carefully for signs of increased drug effect if omeprazole is used with these drugs. In addition, 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.
    Polyethylene Glycol; Electrolytes; Bisacodyl: (Minor) 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. (Minor) The concomitant use of bisacodyl tablets with antacids can cause the enteric coating of the bisacody tablet to dissolve prematurely, leading to possible gastric irritation or dyspepsia. Avoid antacids within 1 hour before or after the bisacodyl dosage.
    Polysaccharide-Iron Complex: (Major) Antacids may decrease the absorption of oral iron preparations. At higher pH values, iron is more readily ionized to its ferric state and is more poorly absorbed. Doses of antacids and iron should be taken as far apart as possible to minimize the potential for interaction.
    Ponatinib: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids 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. (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as omeprazole, 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. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, omeprazole.
    Posaconazole: (Major) 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.
    Potassium Citrate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Potassium Iodide, KI: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Potassium Phosphate; Sodium Phosphate: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Potassium Salts: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Potassium: (Major) There is an increased risk of developing hyperkalemia with the concurrent use of potassium salts and other products that contain a potassium salt, including citric acid; potassium citrate; sodium citrate. If these drugs must be coadministered, regularly monitor the serum potassium concentration and for signs/symptoms of hyperkalemia (muscle weakness, chest pain, or an abnormal heart rhythm).
    Potassium-sparing diuretics: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Primidone: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Propantheline: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Propranolol: (Major) Antacids may reduce the absorption of propranolol. The need to stagger doses of propranolol has not been established, but may be prudent. Monitor clinical response, and adjust propranolol dosage if needed to attain therapeutic goals.
    Pseudoephedrine: (Minor) Pseudoephedrine renal elimination is susceptible to changes in urinary pH. Urinary alkalinizers allow for increased tubular reabsorption of pseudoephedrine. Concomitant administration of pseudoephedrine with urinary alkalinizers may increase the likelihood of pseudoephedrine adverse reactions.
    Pyridoxine, Vitamin B6: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Quazepam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as quazepam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Quinapril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Quinidine: (Major) Urinary alkalinization increases the renal tubular reabsorption of quinidine, resulting in higher quinidine serum concentrations which may lead to toxicity. Avoid citric acid; potassium citrate; sodium citrate administration to any patient receiving treatment with quinidine.
    Quinine: (Major) Antacids may delay or decrease the absorption of quinine.
    Ramipril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Red Yeast Rice: (Moderate) Caution is warranted when combining red yeast rice (structurally similar to lovastatin) with omeprazole. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product.
    Ribociclib: (Minor) Use caution if coadministration of ribociclib with omeprazole is necessary, as the systemic exposure of omeprazole may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and omeprazole is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Minor) Use caution if coadministration of ribociclib with omeprazole is necessary, as the systemic exposure of omeprazole may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and omeprazole is a CYP3A4 substrate.
    Rifabutin: (Major) 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: (Major) 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. (Moderate) Concomitant use of sodium bicarbonate and rifampin may decrease the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of sodium bicarbonate.
    Rifamycins: (Major) 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: (Major) 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.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and omeprazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Severe) 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. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
    Riluzole: (Minor) The principal isozyme involved in the initial oxidative metabolism of riluzole is CYP1A2. CYP1A2 inducers, such as omeprazole could increase the rate of clearance of riluzole. Monitor for decreased effects of riluzole.
    Risedronate: (Major) 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: (Moderate) Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. (Moderate) Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and omeprazole may result in increases in rivaroxaban exposure and may increase bleeding risk. Omeprazole is an inhibitor of P-gp, and rivaroxaban is a substrate of P-gp. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Rosuvastatin: (Major) Coadministration of rosuvastatin with antacids has reduced rosuvastatin plasma concentrations by 54%. When the antacid is given 2 hours after rosuvastatin, no significant change in rosuvastatin plasma concentrations is observed.
    Sacubitril; Valsartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    S-adenosyl-L-methionine, SAM-e: (Minor) Antacids are known to interfere with the absorption of many agents and could theoretically interfere with the oral absorption of SAM-e. It may be prudent for patients to separate the administration of antacids and SAM-e products.
    Salsalate: (Moderate) Urinary alkalinizing agents may increase the excretion of salicylates by increasing renal clearance.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and omeprazole as coadministration may result in increased systemic exposure of omeprazole. Omeprazole is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of omeprazole.
    Saquinavir: (Major) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Secretin: (Major) 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.
    Sibutramine: (Moderate) According to the manufacturer, data from a pharmacokinetic study indicate that omeprazole decreases the metabolism of sibutramine and its active metabolites (M1 and M2). Increases in the serum concentration of sibutramine and its metabolites may lead to an increased risk of sibutramine-related adverse reactions.
    Simeprevir: (Minor) Simeprevir, a P-glycoprotein (P-gp) and a mild intestinal CYP3A4 inhibitor, may increase the side effects of omeprazole, which is a P-gp and CYP3A4 substrate. Additionally, increased side effects of simeprevir may occur as omeprazole is a P-gp inhibitor and simeprevir is a P-gp substrate in vitro. Monitor patients for adverse effects of omeprazole, such as GI events, and simeprevir, such as rash and phototoxicity.
    Simvastatin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Simvastatin; Sitagliptin: (Moderate) Atorvastatin, lovastatin, and simvastatin are HMG-CoA reductase inhibitors (statins) recognized as substrates and inhibitors of the P-glycoprotein (P-gp) transport system. Likewise, studies show that lansoprazole, omeprazole, and pantoprazole are also substrates and inhibitors of P-gp. Due to competitive inhibition of the P-gp transport system, coadministration may lead to increased intestinal absorption and/or decreased hepatic excretion of either product. The resulting increased drug bioavailability could lead to increased adverse events, including serious myopathies in the case of higher than normal statin plasma concentrations. For example, P-gp inhibition was suspected in a case report involving a patient presenting to the emergency room with rhabdomyolysis, causing third-degree AV block. The patient's medication history included atorvastatin (> 1 year history), esomeprazole (6-week history), and clarithromycin (500 mg x 3 doses prior to admission). Symptoms of weakness, shortness of breath, and chest pain coincided with the start of esomeprazole therapy. Due to the timing of symptom onset, clinicians suspected that esomeprazole likely increased atorvastatin plasma concentrations leading to rhabdomyolysis and further complications. Although competitive inhibition of CYP isoenzyme metabolism could have played a minor role in the interaction, the main pathway was thought to be competitive P-gp inhibition. Caution is therefore warranted when combining atorvastatin, lovastatin, red yeast rice (structurally similar to lovastatin), or simvastatin with esomeprazole, lansoprazole, omeprazole, or pantoprazole. Substituting with dexlansoprazole or rabeprazole may represent a safer alternative. Treatment with pravastatin, fluvastatin, and rosuvastatin may also decrease the risk of a P-gp interaction.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Major) Antacids may decrease the absorption of oral iron preparations. At higher pH values, iron is more readily ionized to its ferric state and is more poorly absorbed. Doses of antacids and iron should be taken as far apart as possible to minimize the potential for interaction.
    Sodium Fluoride: (Moderate) Absorption of sodium fluoride may be reduced by concomitant use of antacids. An interval of at least 2 hours is advisable between administration of sodium fluoride and antacids.
    Sodium Polystyrene Sulfonate: (Moderate) Sodium polystyrene sulfonate should be used cautiously with other agents that can induce hypokalemia such as loop diuretics, insulins, or intravenous sodium bicarbonate. Because of differences in onset of action, sodium polystyrene sulfonate is often used with these agents. With appropriate monitoring, hypokalemia can be avoided.
    Sofosbuvir; Velpatasvir: (Major) 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.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) 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. (Moderate) Plasma concentrations of omeprazole, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Solifenacin: (Moderate) 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: (Minor) 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.
    Sotalol: (Major) Coadministration of antacids with sotalol reduces the Cmax and AUC of sotalol by 26% and 20%, respectively. This interaction results in a 25% reduction in the bradycardic effect of sotalol (measured at rest). Administer magnesium hydroxide two hours after the sotalol dose to avoid altering sotalol pharmacokinetics or pharmacodynamics.
    Spironolactone: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    St. John's Wort, Hypericum perforatum: (Major) 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.
    Sucralfate: (Major) Antacids can interfere with the binding capacity of sucralfate to the GI mucosa, decreasing its effectiveness. Antacids should not be administered within 30 minutes of sucralfate. (Minor) Proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. Sucralfate has been shown to delay absorption and reduce the bioavailability of omeprazole by about 16%.
    Tacrolimus: (Major) Addition of tacrolimus to solutions containing sodium bicarbonate or magnesium oxide will result in pH-dependent degradation of tacrolimus.Separation of the oral tacrolimus and antacid doses by at least 2 hours may not be necessary, but more data are needed. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment. (Moderate) Concomitant administration of omeprazole and tacrolimus may increase the serum concentrations of tacrolimus.
    Tamoxifen: (Moderate) Theoretically, concomitant use may result in increased omeprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Omeprazole is a CYP2C19 inhibitor and, in vitro, an inhibitor of CYP2C9. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and 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, omeprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering omeprazole with telaprevir due to an increased potential for omeprazole-related adverse events. If omeprazole 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 omeprazole. Omeprazole is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated omeprazole plasma concentrations.
    Telithromycin: (Minor) Concentrations of omeprazole may be increased with concomitant use of telithromycin. Omeprazole is a CYP3A4 and P-glycoprotein (PGP) substrate and telithromycin is a strong CYP3A4 inhibitor and potential PGP inhibitor. Patients should be monitored for increased side effects.
    Telmisartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and omeprazole is necessary, as the systemic exposure of omeprazole may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of omeprazole as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of omeprazole if necessary. Omeprazole is a CYP3A4 substrate. 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. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and omeprazole is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with omeprazole is necessary, and monitor for an increase in temsirolimus- and omeprazole-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate/inhibitor in vitro, while omeprazole is also a P-gp substrate/inhibitor. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp inhibitors or substrates, but exposure to both omeprazole and temsirolimus (and active metabolite, sirolimus) is likely to increase.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as omeprazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Tetracyclines: (Major) Early reports noted an increase in the excretion of tetracyclines during coadministration with sodium bicarbonate, and that the oral absorption of tetracyclines is reduced by sodium bicarbonate via increased gastric pH. However, conflicting data have been reported, and further study is needed. Two recent studies show no effect of oral sodium bicarbonate administration on tetracycline oral bioavailability. In one of these trials, coadministration with sodium bicarbonate was reported to have no effect on tetracycline urinary excretion, Cmax, or AUC. Until more information is available, avoid simultaneous administration of sodium bicarbonate and tetracyclines. When concurrent therapy is needed, stagger administration times by several hours to minimize the potential for interaction, and monitor for antimicrobial efficacy.
    Thiazide diuretics: (Moderate) 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: (Major) Avoid coadministration of omeprazole with barbiturates because it can result in decreased efficacy of omeprazole. Omeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19.
    Thiothixene: (Major) Antacids may reduce the oral availablility of thiothixene. To avoid this, administer thiothixene at least 1 hour before or 2 hours after the antacid.
    Thyroid hormones: (Major) Antacids have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Administer thyroid hormones at least 4 hours before or after antacids. (Moderate) The use of proton pump inhibitors may result in decreased effectiveness of thyroid hormone therapy. Monitor clinically for signs and symptoms of hypothyroidism and altered response to thyroid hormone therapy. Periodically assess the TSH during use of these drugs together. Gastric acidity is an essential requirement for proper and adequate absorption of levothyroxine and other thyroid hormones. Proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce thyroid hormone absorption.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and omeprazole may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and omeprazole is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Ticlopidine: (Major) Administration of ticlopidine after antacids results in a decrease in plasma levels of ticlopidine. Staggering the times of administration may avoid this pharmacokinetic interaction.
    Tipranavir: (Moderate) 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.
    Tirofiban: (Minor) Patients who receive omeprazole concomitantly with tirofiban may have a higher rate of tirofiban clearance than patients who do not receive omeprazole. The clinical significance of this is unknown.
    Tocilizumab: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. In clinical trials of patients taking both omeprazole and tocilizumab, a decrease in omeprazole exposure (AUC) was noted. One week after a single tocilizumab dose, a 12 to 28% decrease in omeprazole exposure occurred. Use caution when using tocilizumab in combination with CYP-metabolized drugs where a decrease in effectiveness is undesirable.
    Tolmetin: (Major) The bioavailability of tolmetin is decreased by sodium bicarbonate. Do not use a sodium bicarbonate containing antacid concurrently with tolmetin.
    Tolterodine: (Moderate) 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.
    Topotecan: (Major) Avoid the concomitant use of omeprazole, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. The pharmacokinetics of topotecan are unchanged when coadministered with ranitidine, which is a possible alternative to acid suppression therapy if needed. If coadministration of omeprazole and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea; this also applies to combination products containing omeprazole, such as amoxicillin; clarithromycin; omeprazole and omeprazole; sodium bicarbonate. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Torsemide: (Moderate) 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.
    Trandolapril: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Trandolapril; Verapamil: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as ACE inhibitors. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Triamterene: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as potassium-sparing diuretics. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function.
    Triazolam: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as triazolam. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
    Trihexyphenidyl: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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: (Moderate) Antacids may inhibit the oral absorption of antimuscarinics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction. (Moderate) 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.
    Ulipristal: (Minor) In vitro data indicate that ulipristal may be an inhibitor of P-glycoprotein (P-gp) at clinically relevant concentrations. Thus, co-administration of ulipristal and P-gp substrates such as omeprazole may increase omeprazole concentrations. With single doses of ulipristal for emergency contraception it is not clear this interaction will have clinical consequence. In the absence of clinical data, co-administration of ulipristal (when given daily) and P-gp substrates is not recommended.
    Valproic Acid, Divalproex Sodium: (Minor) Sodium bicarbonate may increase valproic acid AUC. Patients should be monitored for adverse effects in this situation.
    Valsartan: (Major) Products containing a potassium salt, including citric acid; potassium citrate; sodium citrate, should be used with caution in patients taking drugs that may increase serum potassium concentrations, such as angiotensin II receptor antagonists. Concurrent use can cause hyperkalemia, especially in elderly patients or patients with impaired renal function. Coadministration may also result in increases in serum creatinine in heart failure patients.
    Vandetanib: (Minor) Use caution if coadministration of vandetanib with omeprazole is necessary, due to a possible increase in omeprazole-related adverse reactions. Omeprazole is partially a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate, by 29% and 23%, respectively.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and omeprazole. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and may be a P-gp inhibitor at therapeutic dose levels in the gut; omeprazole is a P-gp inhibitor and substrate. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering omeprazole at least 6 hours before venetoclax. If omeprazole is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Vincristine Liposomal: (Major) Omeprazole inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Major) Omeprazole inhibits P-glycoprotein (P-gp), and vincristine is a P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vinorelbine: (Moderate) Use caution with concurrent use of omeprazole, a P-glycoprotein (P-gp) inhibitor, and vinorelbine, a P-gp substrate, as the metabolism of vinorelbine may be decreased; this may also apply to combination products containing omeprazole, including amoxicillin; clarithromycin; omeprazole and omeprazole; sodium bicarbonate. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    Voriconazole: (Moderate) Reduce the omeprazole dose by one-half when initiating voriconazole therapy in patients who are currently receiving omeprazole at doses of 40 mg/day or greater. Levels of omeprazole may increase by up to 2-fold due to CYP2C19 and CYP3A4 inhibition by voriconazole.
    Warfarin: (Moderate) 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.
    Zinc Salts: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and omeprazole is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Omeprazole; sodium bicarbonate is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies on the use of omeprazole; sodium bicarbonate in pregnancy. Animal reproductive studies have been conducted with omeprazole and esomeprazole. Rats and rabbits dosed with esomeprazole up to 57 and 35 times, respectively, that of humans based on body surface area, showed no evidence of teratogenicity. However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses >= 33.6 times an oral human dose of 40 mg. Although animal studies are not always predictive of human effects, because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole use in pregnancy should be limited. In humans, omeprazole is known to cross the placenta to the fetus. Epidemiological evaluations have compared the rate of congenital abnormalities and stillbirths among infants exposed to omeprazole during pregnancy to similar findings for infants exposed to H2-receptor antagonists or other controls. Overall, slightly higher rates of congenital malformations (e.g., ventricular septal defects) and number of stillborn infants have been reported for cases where exposure to omeprazole occured in the first trimester of pregnancy and beyond. Although no untoward effects have been observed in humans, chronic use of sodium bicarbonate may lead to systemic alkalosis, and increased sodium intake can produce edema and weight increase. Use of omeprazole; sodium bicarbonate during pregnancy should be limited to cases where the benefit to the mother outweighs any potential risk to the fetus. If possible, avoid use in the first three months of pregnancy. 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.

    According to the manufacturer, it is advisable to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. Omeprazole is excreted into human breast milk and there is a potential for adverse reactions in the nursing infant, including suppression of gastric acid secretion. The manufacturer of omeprazole; sodium bicarbonate also states that sodium bicarbonate should be used use caution in breast-feeding mothers. Alternative therapies for consideration include antacids and H2 blockers. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Omeprazole belongs to the class of GI antisecretory agents, the substituted benzimidazoles, that suppress gastric acid secretion by inhibiting the H+/K+ ATPase enzyme system of parietal cells. Omeprazole is a lipophilic weak base (pKa 4) and is transformed into an active acidic sulfonamide form when exposed to acidic conditions. Following activation, omeprazole binds selectively and irreversibly to the H+/K+ ATPase pump on the secretory surface of the parietal cell membrane. Subsequently, the secretion of hydrogen ions into the gastric lumen is inhibited. Omeprazole is characterized as a gastric acid or proton pump inhibitor (PPI) because it blocks the final step of gastric acid production. This effect is dose-dependent and leads to the inhibition of both basal and stimulus-induced acid secretion. As with all PPIs, omeprazole is acid-labile and is rapidly degraded by gastric acid. Conventional PPIs are enteric-coated to avoid degradation, while Zegerid suspension and capsules (omeprazole; sodium bicarbonate) contain non-enteric coated omeprazole powder. By administering omeprazole with sodium bicarbonate, omeprazole is protected against acid degradation until it can be absorbed. Furthermore, the concomitant administration of omeprazole with sodium bicarbonate may also provide a temporary stimulus to gastrin release which may stimulate the parietal cell mass and promote omeprazole entry into and inhibition of the H+/K+ ATPase pumps. Sodium bicarbonate may be responsible for the rapid rise in intragastric pH seen after administration, while prolonged antisecretory effects are due to omeprazole absorption.
     
    Treatment with omeprazole; sodium bicarbonate (Zegerid) is highly effective at reducing the production of gastric acid, measured by the percent decrease from baseline in 24 hour integrated gastric acidity. Following administration of a repeated once daily dose of 40 mg and 20 mg omeprazole; sodium bicarbonate in healthy subjects, the 24 hour integrated gastric acidity (mmol*hr/L) is 84% and 82%, respectively. During a 14 day trial, the majority of critically ill patients have documented gastric pH values >= 4 while receiving 40 mg Zegerid oral suspension administered once daily via gastric tube. Approximately 99% and 92% of patients have gastric pH values >= 4 measured at 1—2.5 and 6 hours after the first dose, respectively. The antisecretory effects last longer than would be expected from the very short plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme.
     
    Serum gastrin concentrations increase during the initial 1—2 weeks of therapy, and median increases in gastrin are greater than the increases produced by H2-receptor antagonists. Gastrin levels return to baseline within 1—2 weeks following discontinuation of therapy. Although prolonged hypergastrinemia has been associated with gastric tumors, long-term studies of proton pump inhibitors have not revealed an increased development of tumors, which was an initial concern in animal models.

    PHARMACOKINETICS

    Omeprazole; sodium bicarbonate is administered orally.
     
    Omeprazole is approximately 95% bound to plasma proteins. Extensive hepatic metabolism occurs, and the metabolites have minimal antisecretory activity. In healthy subjects, the mean plasma half-life is 1 hour. Approximately 77% of a dose is eliminated in the urine as metabolites, and the remainder of the dose is excreted in the feces. It is not known if omeprazole; sodium bicarbonate crosses the placenta, but it is excreted into breast milk.

    Oral Route

    Omeprazole; sodium bicarbonate should be taken on an empty stomach. Absorption is rapid, with mean peak plasma concentrations of omeprazole (Tmax) occurring at about 30 minutes after a single dose or repeated administration. After a two-dose 40 mg loading regimen, the AUC approximately doubles after the second 40 mg dose. A greater than linear mean increase in AUC (3-fold increase) is observed when doubling the dose from 20 mg to 40 mg. When omeprazole; sodium bicarbonate is administered 1 hour after a meal, the Cmax and AUC are reduced by approximately 62% and 26%, respectively, compared to administration on an empty stomach. The absolute bioavailability is 30—40% at doses of 20—40 mg, due in large part to first-pass metabolism. The onset of action of omeprazole; sodium bicarbonate is about 1 hour, and the duration of action is > 72 hours. Gastrointestinal secretory activity returns to normal 3—5 days after therapy is discontinued.