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    Combinations for Treatment of Helicobacter pylori

    DEA CLASS

    Rx

    DESCRIPTION

    Amoxicillin capsules, clarithromycin immediate-release tablets, and omeprazole delayed-release capsules are a triple-drug regimen containing an aminopenicillin, a macrolide, and a PPI
    Used for the eradication of H. pylori
    Triple-drug regimens are recommended by the American College of Gastroenterology (ACG) guidelines for managing H. pylori infection

    COMMON BRAND NAMES

    Omeclamox

    HOW SUPPLIED

    Omeclamox Oral Cap DR Pellets: 500-500-20mg
    Omeclamox Oral Cap: 500-500-20mg
    Omeclamox Oral Tab: 500-500-20mg

    DOSAGE & INDICATIONS

    For Helicobacter pylori (H. pylori) eradication in the treatment of patients with duodenal ulcer disease (active or a one-year history of duodenal ulcer), gastric ulcer†, or gastric mucosa associated lymphoid tissue (MALT) lymphoma†.
    NOTE: The American College of Gastroenterology (ACG) recommends 10 to 14 days of a triple-drug regimen containing a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole. Although 10 to 14 days is recommended, ACG also indicates that giving therapy for 2 weeks may be preferred; a meta-analysis of more than 900 patients found that, as compared to a 7-day regimen, the rate of H. pylori eradication was significantly higher in patients taking triple therapy for 14 days (odds ratio: 0.62, 95% CI: 0.45 to 0.84). Although not significant, there was a trend towards improved eradication rates with 10 days of therapy vs. 7 days of therapy. The same combination for 14 days continues to be recommended as first line therapy in the 2006 global updates from the Maastricht III Consensus Report.
    NOTE: In populations where H. pylori infection is common (10% or more), patients presenting with non-ulcer dyspepsia should be tested for H. pylori; those found to be H. pylori positive should be started on combination eradication therapy.
    NOTE: Clarithromycin resistance rates for H. pylori strains in the US are 13%. In patients who fail amoxicillin; clarithromycin; omeprazole therapy, consider susceptibility testing; if resistance to clarithromycin is demonstrated, a non-clarithromycin containing regimen is recommended.
    NOTE: Bismuth preparations, some antimicrobials, and some PPIs suppress H. pylori. Ingestion of these substances within 4 weeks prior to performing urease or breath-tests for H. pylori detection may lead to false negative results. In the 4 weeks prior to performing the test, the patient must avoid the use of amoxicillin; clarithromycin; omeprazole and other agents known to suppress H. pylori.
    NOTE: A large body of data exist to support the importance of H. pylori eradication as the first line treatment of gastric MALT lymphoma. Following H. pylori eradication, long term tumor regression is observed in 60% to 90% of patients.
    Oral dosage
    Adults

    Amoxicillin 1,000 mg PO, clarithromycin 500 mg PO, and omeprazole 20 mg PO given twice daily prior to eating for 10 to 14 days (total daily dose: amoxicillin 2,000 mg/day, clarithromycin 1,000 mg/day, omeprazole 40 mg/day). Clarithromycin-containing regimens are associated with a high eradication rate and fewer side effects than regimens that include metronidazole. In patients with an active ulcer at time of therapy initiation, an additional 18 days of omeprazole 20 mg once daily is recommended.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Amoxicillin 2000 mg/day PO; Clarithromycin 1 g/day PO; Omeprazole 40 mg/day PO.

    Geriatric

    Amoxicillin 2000 mg/day PO; Clarithromycin 1 g/day PO; Omeprazole 40 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.
     

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    According to the manufacturer, Omeclamox-Pak (amoxicillin, clarithromycin and omeprazole in pre-packaged combination) therapy is not recommended in patients with hepatic impairment, due to the fixed dosages contained in the product.

    Renal Impairment

    CrCl >= 30 mL/min: No dosage adjustment needed.
    CrCl < 30 mL/min: Omeclamox-Pak is not recommended due to the fixed dosages within the packaging; both amoxicillin and clarithromycin require dose and/or interval adjustments for significant renal impairment.

    ADMINISTRATION

    Oral Administration

    Administer amoxicillin; clarithromycin, omeprazole (Omeclamox-Pak) doses before eating, once in the morning and evening.
    Instruct patients to swallow each tablet or capsule whole.

    STORAGE

    Omeclamox:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the use of the amoxicillin; clarithromycin; omeprazole combination pack. Clinicians may wish to consult the individual monographs for more information.
     
    Omeclamox Pak contains amoxicillin. A false-positive reaction for glucose in the urine has been observed in patients receiving penicillins, such as amoxicillin, and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, or Diastix). Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on amoxicillin treatment.
     
    Omeclamox Pak contains amoxicillin, clarithromycin, and omeprazole. Antimicrobials and omeprazole or other PPIs, as well as bismuth preparations, suppress H. pylori. Administration of these agents within 4 weeks prior to performing urease or breath-tests for H. pylori detection may lead to false negative results. In the 4 weeks prior to performing the test, the patient must avoid the use of agents which are known to suppress H. pylori.

    Macrolide hypersensitivity

    Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) contains clarithromycin, a macrolide antimicrobial, and therefore is contraindicated in patients who have shown macrolide hypersensitivity. Clarithromycin can cause rare, but serious allergic reactions, including angioedema and anaphylaxis. There is a risk of cross sensitivity with other macrolide antibiotics.

    Asthma, carbapenem hypersensitivity, cephalosporin hypersensitivity, eczema, penicillin hypersensitivity, urticaria

    Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) contains amoxicillin, a penicillin, and therefore is contraindicated in patients who have shown penicillin hypersensitivity. Amoxicillin should also be used cautiously in patients with other beta-lactam related hypersensitivities, such as cephalosporin hypersensitivity and carbapenem hypersensitivity. These patients are more susceptible to hypersensitivity reactions during therapy with amoxicillin. Patients with allergies or allergic conditions including asthma, eczema, hives (urticaria), or hay fever may have a greater risk for hypersensitivity reactions to penicillins.

    Proton pump inhibitors (PPIs) hypersensitivity

    Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) contains omeprazole and therefore is contraindicated in patients who have shown omeprazole hypersensitivity. Omeprazole is a proton pump inhibitor (PPI) and should be used with caution 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).

    Colitis, diarrhea, GI bleeding, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) should be used with caution in patients with a history of GI disease. Patients with colitis may have an exacerbation of their condition because of the adverse GI effects associated with antimicrobial therapy. Diarrhea, often associated with antibiotic therapy, usually resolves after the discontinuation of therapy. However, some patients develop watery and bloody stools indicative of GI bleeding shortly after starting antibiotic treatment and even as late as a couple months after ending treatment. If this occurs, advise patients to contact their physicians as soon as possible, as this may be a sigh of antibiotic-associated colitis. Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis), which may range in severity from mild to life-threatening. Additionally, gastric acid suppression has been proposed as an independent risk factor for the development of Clostridium difficile-associated disease (CDAD), particularly with proton pump inhibitors; however, studies have shown conflicting results. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Gastric cancer

    Symptomatic response to therapy with Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) does not preclude the presence of gastric cancer or other malignancy.

    Hepatic disease

    According to the manufacturer, Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in fixed dose, prepackaged combination) should be avoided in patients with hepatic disease. Production of the active metabolite of clarithromycin is reduced in these patients. Excretion of clarithromycin is via the liver and the kidneys. Dose reductions of clarithromycin, however, are not recommended for patients with hepatic impairment providing they do not have coexisting renal dysfunction. Further, the bioavailability of omeprazole is significantly increased in patients with chronic hepatic disease, reflecting decreased first-pass effect. Increased omeprazole half-life and reduced plasma clearance is also observed in patients with hepatic impairment. Abnormal liver-function tests have been reported with omeprazole use. Renal, hepatic, and hematopoietic function should be assessed periodically during therapy.

    Renal failure, renal impairment

    Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) should be used with caution in patients with renal impairment since both amoxicillin and clarithromycin are eliminated via renal mechanisms, and dosage adjustments are recommended in the presence of renal dysfunction. Renal function should be assessed periodically during therapy. Omeclamox-Pak use is not recommended in patients with renal failure or CrCl < 30 ml/min since dosages in the packaging are fixed, and dosage intervals are not easily adjusted to recommended dosages for renal dysfunction.

    Leukemia, mononucleosis, viral infection

    Omeclamox-Pak contains amoxicillin; clarithromycin; omeprazole in prepackaged combination. Amoxicillin should be used with caution in patients with lymphatic leukemia because these patients may be more likely to develop an amoxicillin-associated rash. Patients with viral infection such as CMV, viral respiratory infections, and especially mononucleosis have a high incidence of reported rashes.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease, torsade de pointes, ventricular arrhythmias

    Due to the potential for QT prolongation, avoid clarithromycin in patients with congenital or acquired QT prolongation syndromes or in patients with a history of ventricular arrhythmias, including torsade de pointes (TdP). Patients taking concurrent medications that increase the QT interval and are metabolized by CYP3A4 should be closely monitored; concurrent administration of clarithromycin with certain other drugs is contraindicated (e.g., astemizole, cisapride, pimozide, and terfenadine). Use clarithromycin with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Additionally, an increase in all-cause mortality up to 10 years after clarithromycin exposure (hazard ratio 1.10; 95% CI 1 to 1.21) was observed in a clinical trial of patients with coronary artery disease. The cause of the increased mortality has not been established. Omeprazole has also been reported to cause hypomagnesemia. Use proton pump inhibitors (PPIs) with caution and, if possible, avoid long-term (more than 14 days) use in patients with congenital long QT syndrome, as they may be at higher risk for arrhythmias.

    Myasthenia gravis

    Omepclamox-Pak contains amoxicillin; clarithromycin; omeprazole in prepackaged combination. Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome have been reported in patients receiving clarithromycin therapy. Therefore, caution is warranted when treating patients with existing myasthenic syndrome with Omeclamox-Pak combination therapy.

    Osteoporosis

    Omepclamox-Pak contains amoxicillin; clarithromycin; omeprazole in prepackaged combination. Use proton pump inhibitors (PPIs), such as omepraole, cautiously in patients with or who have risk factors for osteoporosis. PPIs have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. There have been six epidemiological studies that 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. Depending on the study, exposure to PPIs ranged between 1–12 years. The emergence of fractures varied among studies; one study reported an increase in fractures with use of PPIs in the previous year and another study found an increase after 5–7 years of PPI use. Increased risk was primarily observed in patients >= 50 years old, patients taking prescription PPIs for at least one year, and patients who had been taking high doses (doses greater than those recommended with OTC use). Alternatively, in another epidemiological study with similar study design, a relationship between PPI use and fractures was not established; however, the study population did not have major risk factors for fracture at study entry. It should be noted that randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; some limitations of these RCTs were study duration (generally six months) and insufficient information on effects of higher than recommended doses. Until more data are available, 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 osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

    Geriatric

    Omepclamox-Pak contains amoxicillin; clarithromycin; omeprazole in prepackaged combination. In geriatric patients, the elimination rate of omeprazole is decreased and bioavailability increased, possibly an effect of asymptomatic renal and hepatic dysfunction. Therefore, use Omeclamox-Pak with caution in this population. 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).

    Pregnancy

    Omepclamox-Pak contains amoxicillin; clarithromycin; omeprazole in prepackaged combination. The product is classified in FDA pregnancy risk category C, based on the pregnancy category for omeprazole and clarithromycin. Substantial animal data demonstrate clarithromycin-associated toxicity to the embryo. Toxicity occurred in monkeys, rats, mice, and rabbits when clarithromycin was given in doses producing serum concentrations of 2—17 times those resulting from the maximum recommended dose in humans. If patients become pregnant, they should be warned of the possible hazards of taking clarithromycin during pregnancy. Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted; this effect may also occur with amoxicillin. Except in very unusual cases, H. pylori eradication treatment can generally be deferred until after delivery.

    Breast-feeding

    Omepclamox-Pak contains amoxicillin; clarithromycin; omeprazole in prepackaged combination. The manufacturer recommends that a decision should be made whether to discontinue nursing or to discontinue the drug product, taking into account the potential risk to the infant versus the potential benefit to the mother. In general, this combination product would be best avoided during lactation. Amoxicillin, is excreted in breast milk and may rarely cause diarrhea, candidiasis, and skin rash or other sensitizations in breast-feeding infants; however, amoxicillin use in lactation is considered low risk by the American Academy of Pediatrics (AAP). Clarithromycin is excreted in the milk of lactating animals; other macrolides are excreted in human milk and clarithromycin has been reported to transfer to human milk in concentrations that are roughly 25% of maternal serum concentrations. Omeprazole is known to be excreted into human breast milk. The clinical effects of infant exposure to omeprazole have not been confirmed. Potentially serious adverse reactions may occur with the use of omeprazole during breast-feeding, including suppression of gastric acid secretion in the nursing infant. There is a paucity of data regarding omeprazole use during lactation.

    Children, infants, neonates

    Safety and efficacy of Omeclamox-Pak (amoxicillin; clarithromycin; omeprazole in prepackaged combination) in neonates, infants, children, and adolescents infected with Helicobacter pylori have not been established.

    Asian patients

    Omeclamox-Pak contains amoxicillin; clarithromycin; omeprazole in a fixed dosage, prepackaged combination. It is usually recommended to consider an omeprazole dose adjustment in Asian patients. Asian patients exhibit a four-fold increase in AUC of omeprazole compared to Caucasians. The manufacturer of Omeclamox-Pak states that the use of this product in fixed dosage should be avoided unless it is deemed that the benefits outweigh the risks.

    Systemic lupus erythematosus (SLE)

    Omeclamox-Pak contains amoxicillin, clarithromycin, and omeprazole. 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

    azotemia / Delayed / 4.0-4.0
    pancreatitis / Delayed / 0-1.0
    seizures / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    serum sickness / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    interstitial nephritis / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    bronchospasm / Rapid / 0-1.0
    acute generalized exanthematous pustulosis (AGEP) / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    torsade de pointes / Rapid / 0-1.0
    hepatic encephalopathy / Delayed / 0-1.0
    hepatic failure / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    pancytopenia / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    optic atrophy / Delayed / 0-1.0
    lupus-like symptoms / Delayed / Incidence not known

    Moderate

    pseudomembranous colitis / Delayed / 1.0-10.0
    superinfection / Delayed / 1.0-10.0
    constipation / Delayed / 1.5-1.5
    stomatitis / Delayed / 0-1.0
    hallucinations / Early / 0-1.0
    depression / Delayed / 0-1.0
    psychosis / Early / 0-1.0
    mania / Early / 0-1.0
    confusion / Early / 0-1.0
    candidiasis / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    QT prolongation / Rapid / 0-1.0
    peripheral edema / Delayed / 0-1.0
    palpitations / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    angina / Early / 0-1.0
    hepatitis / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    hyponatremia / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    blurred vision / Early / 0-1.0
    crystalluria / Delayed / 0-1.0
    hematuria / Delayed / 0-1.0
    proteinuria / Delayed / 0-1.0
    glycosuria / Early / 0-1.0
    pyuria / Delayed / 0-1.0

    Mild

    diarrhea / Early / 14.0-14.0
    dysgeusia / Early / 10.0-10.0
    headache / Early / 7.0-7.0
    abdominal pain / Early / 2.0-5.2
    nausea / Early / 3.0-4.0
    vomiting / Early / 3.2-3.2
    flatulence / Early / 2.7-2.7
    dyspepsia / Early / 1.9-2.0
    infection / Delayed / 1.9-1.9
    dizziness / Early / 1.5-1.5
    rash (unspecified) / Early / 1.5-1.5
    asthenia / Delayed / 1.3-1.3
    back pain / Delayed / 1.1-1.1
    cough / Delayed / 0-1.1
    xerostomia / Early / 0-1.0
    tooth discoloration / Delayed / 0-1.0
    weight gain / Delayed / 0-1.0
    stool discoloration / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    tremor / Early / 0-1.0
    insomnia / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    anxiety / Delayed / 0-1.0
    vertigo / Early / 0-1.0
    nightmares / Early / 0-1.0
    drowsiness / Early / 0-1.0
    agitation / Early / 0-1.0
    myalgia / Early / 0-1.0
    weakness / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    petechiae / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    maculopapular rash / Early / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    purpura / Delayed / 0-1.0
    photosensitivity / Delayed / 0-1.0
    xerosis / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    malaise / Early / 0-1.0
    fever / Early / 0-1.0
    fatigue / Early / 0-1.0
    gynecomastia / Delayed / 0-1.0
    leukocytosis / Delayed / 0-1.0
    tinnitus / Delayed / 0-1.0
    ocular irritation / Rapid / 0-1.0
    xerophthalmia / Early / 0-1.0
    increased urinary frequency / Early / 0-1.0
    testicular pain / Early / 0-1.0

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Administer clarithromycin and zidovudine at least 2 hours apart. Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine may result in decreased steady-state zidovudine concentrations. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation, such as clarithromycin.
    Abemaciclib: (Major) A dose reduction of abemaciclib is required if coadministration with clarithromycin is necessary due to increased plasma concentrations of abemaciclib. In patients at the recommended starting doses of either 200 mg or 150 mg twice daily, reduce the dose of abemaciclib to 100 mg twice daily. In patients who have already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg twice daily. If clarithromycin is discontinued, resume the original dose of abemaciclib after 3 to 5 half-lives of clarithromycin. Abemaciclib is a CYP3A4 substrate and clarithromycin is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor was predicted to increase exposure to unbound abemaciclib and its active metabolites by 1.7-fold to 2.2-fold.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and clarithromycin; significantly increased acalabrutinib exposure may occur. If short-term clarithromycin use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (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.
    Acarbose: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    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.
    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.
    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. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetaminophen; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Acetaminophen; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Moderate) Coadministration of clarithromycin (a CYP3A4 inhibitor) and oxycodone (a CYP3A4 substrate) may result in increased oxycodone plasma concentrations and a higher risk for adverse or prolonged effects. If coadministration of these agents is necessary, patients should be monitored at frequent intervals and dosage adjustments made if warranted.
    Acetohexamide: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Ado-Trastuzumab emtansine: (Major) Avoid concomitant use of ado-trastuzumab emtansine with clarithromycin, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until clarithromycin is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Clarithromycin is a strong CYP3A4 inhibitor. When a single dose of another CYP3A4 substrate, midazolam, was coadministered with 7 days of clarithromycin, the AUC of IV midazolam increased by 174% and PO midazolam by 600%. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    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. (Moderate) Concomitant use of afatinib, a P-glycoprotein (P-gp) substrate, and clarithromycin, a P-gp inhibitor, may increase the exposure of afatinib. If the use of both agents is necessary, consider reducing the starting afatinib dose to 30 mg/day if the original dose is not tolerated. Resume the previous dose if clarithromycin is discontinued.
    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.
    Alfentanil: (Moderate) Use together with caution. Alfentanil is metabolized by the CYP3A4 isoenzyme. Clarithromycin is an inhibitor of CYP3A4 may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Postmarketing reports of interactions with concomitant use have been noted.
    Alfuzosin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with alfuzosin. Clarithromycin is associated with QT prolongation and TdP. Alfuzosin also has a slight QT prolonging effect, based on electrophysiology studies performed by the manufacturer. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. In addition, alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes; clarithromycin may inhibit alfuzosin metabolism and increase systemic exposure to alfuzosin.
    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.
    Allopurinol: (Minor) Use of amoxicillin with allopurinol can increase the incidence of drug-related skin rash.
    Almotriptan: (Major) Clarithromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Alogliptin; Metformin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Alogliptin; Pioglitazone: (Major) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents. With certain agents, such as pioglitazone and rosiglitazone, inhibition of the CYP3A4 enzyme by clarithromycin may be involved.
    Alosetron: (Moderate) Concomitant use of alosetron with clarithromycin may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; clarithromycin is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
    Alpha-glucosidase Inhibitors: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Alprazolam: (Moderate) Clarithromycin inhibits CYP3A4 and may profoundly decrease alprazolam clearance. Use this combination with caution and consider a dose reduction of alprazolam of up to 50%. (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) The administration of amiloride 2 hours before a dose of amoxicillin oral suspension reduced the bioavailability of amoxicillin by 27% and its Cmax by 25%. No change in the renal clearance of amoxicillin was noted. Although the significance of this pharmacokinetic interaction is unclear, clinicians should avoid administering doses of these two drugs within 2 hours of the other. Staggering the administration times further may avoid this interaction.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) The administration of amiloride 2 hours before a dose of amoxicillin oral suspension reduced the bioavailability of amoxicillin by 27% and its Cmax by 25%. No change in the renal clearance of amoxicillin was noted. Although the significance of this pharmacokinetic interaction is unclear, clinicians should avoid administering doses of these two drugs within 2 hours of the other. Staggering the administration times further may avoid this interaction. (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.
    Amiodarone: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). The concomitant use of amiodarone and other drugs known to prolong the QT interval should only be done after careful assessment of risks versus benefits. If possible, avoid coadministration of amiodarone and clarithromycin. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (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. (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg per day of atorvastatin daily if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin. The AUC of atorvastatin was increased 4.4-fold with the concomitant administration of clarithromycin. (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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (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: (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.
    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.
    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.
    Amprenavir: (Minor) Coadministration of amprenavir with clarithromycin may lead to an increase in the systemic exposure to amprenavir. The clinical significance of this interaction is unknown, and dosage adjustments may not be necessary.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include clarithromycin.
    Anticholinergics: (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.
    Apixaban: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as clarithromycin. Concomitant administration of clarithromycin and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and clarithromycin.
    Apomorphine: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with apomorphine. Clarithromycin is associated with QT prolongation and TdP. Limited data indicate that QT prolongation is also possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2 to 10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of clarithromycin with aprepitant due to substantially increased exposure of aprepitant; increased clarithromycin exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in clarithromycin- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Clarithromycin is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Clarithromycin is also 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; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. (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.
    Aripiprazole: (Major) Because both clarithromycin and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated.
    Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as clarithromycin are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed. (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.
    Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with QT prolongation and TdP. QT prolongation, TdP, and complete atrioventricular block have also been reported with the administration of arsenic trioxide.
    Artemether; Lumefantrine: (Major) Concurrent use of artemether; lumefantrine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if clarithromycin must be used with or after artemether; lumefantrine treatment. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Artemether; lumefantrine is also associated with a possible risk for QT prolongation and TdP. In addition, clarithromycin is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
    Aspirin, ASA: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    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. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    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) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; 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. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response. (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. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Dipyridamole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Oxycodone: (Moderate) Coadministration of clarithromycin (a CYP3A4 inhibitor) and oxycodone (a CYP3A4 substrate) may result in increased oxycodone plasma concentrations and a higher risk for adverse or prolonged effects. If coadministration of these agents is necessary, patients should be monitored at frequent intervals and dosage adjustments made if warranted. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Pravastatin: (Major) Do not exceed 40 mg per day of pravastatin if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Coadministration of clarithromycin increased the AUC and Cmax of pravastatin by 110% and 128%, respectively. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    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) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC).
    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) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC). (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.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include clarithromycin.
    Atorvastatin: (Major) Do not exceed 20 mg per day of atorvastatin daily if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin. The AUC of atorvastatin was increased 4.4-fold with the concomitant administration of clarithromycin. (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.
    Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg per day of atorvastatin daily if coadministration with clarithromycin cannot be avoided. Concurrent use increases the risk of myopathy and rhabdomyolysis. Appropriate clinical assessments should be made to ensure the lowest possible atorvastatin dose is used. Rare reports of rhabdomyolysis have been reported in patients taking clarithromycin and atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of concomitant therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin. The AUC of atorvastatin was increased 4.4-fold with the concomitant administration of clarithromycin. (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.
    Atropine: (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: (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) 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) 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) 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. (Major) There have been spontaneous and/or published reports of interactions between clarithromycin and phenobarbital. Inducers of CYP3A enzymes, such as phenobarbital will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Clinicians should observe patients closely for infection resolution if these drugs are administered concurrently. (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: (Major) Concomitant use of avanafil and clarithromycin is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; clarithromycin would be expected to have similar effects. (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: (Major) Avoid coadministration of axitinib with clarithromycin due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after clarithromycin is discontinued. Axitinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Clarithromycin increased the AUC of another CYP3A4 substrate, midazolam, by 174% after IV administration and by 600% after oral administration. Coadministration with another strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. (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.
    Azelastine; Fluticasone: (Moderate) Fluticasone oral inhalation is a CYP3A4 substrate and caution is warranted with coadministration of very potent CYP3A4 inhibitors, such as clarithromycin. Patients may need to be observed for increased corticosteroid-related side effects. Coadministration of another potent CYP3A4 inhibitor (ketoconazole) with fluticasone oral inhalation resulted in increased fluticasone concentrations and reduced plasma cortisol AUC.
    Azilsartan; 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.
    Azithromycin: (Major) Both clarithromycin and azithromycin are macrolide antibiotics and coadministration would represent duplicate therapy. Additionally, coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP, and cases of QT prolongation and TdP have been reported during post-marketing use of 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.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of clarithromycin could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
    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.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as clarithromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, clarithromycin may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) The concurrent use of clarithromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Ergotamine is primarily metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with other strong CYP3A4 inhibitors. (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. (Major) There have been spontaneous and/or published reports of interactions between clarithromycin and phenobarbital. Inducers of CYP3A enzymes, such as phenobarbital will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OHclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. Clinicians should observe patients closely for infection resolution if these drugs are administered concurrently. (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) The American College of Gastroenterology states that the effectiveness of proton pump inhibitors (PPIs) may be theoretically decreased if given with other antisecretory agents (e.g., anticholinergics). Proton pump inhibitors (PPIs) inhibit only actively secreting H+-pumps.
    Benazepril; Hydrochlorothiazide, HCTZ: (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: (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) 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.
    Bepridil: (Severe) According to the manufacturer, bepridil is contraindicated for use with drugs that prolong the QT interval, such as clarithromycin, due to the risk of torsades de pointes.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving clarithromycin. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving clarithromycin. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; clarithromycin inhibits P-gp.
    Bexarotene: (Major) Coadministration of bexarotene and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, bexarotene is metabolized by cytochrome P450 3A4. Clarithromycin is an inhibitor of CYP3A4 and would be expected to increase bexarotene plasma concentrations following oral/systemic administration.
    Bicalutamide: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as clarithromycin, decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
    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.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clarithromycin. (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: (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: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include clarithromycin. (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.
    Boceprevir: (Major) Close clinical monitoring is advised when administering clarithromycin with boceprevir due to an increased potential for serious clarithromycin-related adverse events, such as QT prolongation and torsade de pointes. No clarithromycin dosage adjustments are required for patients with normal renal function. If clarithromycin dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of clarithromycin and boceprevir. Both clarithromycin and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, clarithromycin is an inhibitor of P-glycoprotein (P-gp), and efflux transporter partially responsible for the metabolism of boceprevir. When used in combination, the plasma concentrations of both medications may be elevated. (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. (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and may increase the serum concentration of CYP3A4 substrates, such as bortezomib, due to the potential for reduced metabolism and drug accumulation.
    Bosentan: (Major) Coadministration of bosentan and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Coadministration may also increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored. (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) Avoid concomitant use of bosutinib and clarithromycin; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. (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.
    Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level. Similar precautions apply to combination products containing clarithromycin such as amoxicillin; clarithromycin; lansoprazole or amoxicillin; clarithromycin; omeprazole.
    Brigatinib: (Major) Avoid coadministration of brigatinib with clarithromycin if possible due to increased plasma exposure of brigatinib and decreased exposure to clarithromycin. Alternative antibacterial treatment should be considered. If concomitant use is unavoidable, monitor response to clarithromycin and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of clarithromycin, resume the brigatinib dose that was tolerated prior to initiation of clarithromycin. Brigatinib is a CYP3A4 substrate and inducer; clarithromycin is a substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. CYP3A4 inducers decrease the plasma concentrations of clarithromycin and increase those of 14-OH-clarithromycin. Because this metabolite has different antimicrobial activity compared to clarithromycin, the intended therapeutic effect of clarithromycin could be decreased.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with clarithromycin ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; clarithromycin is a strong inhibitor of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Budesonide: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (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: (Moderate) Avoid coadministration of oral budesonide and clarithromycin due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (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.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and clarithromycin may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; clarithromycin inhibits CYP3A4.
    Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of clarithromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Clarithromycin also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as clarithromycin may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Buspirone: (Moderate) Concomitant administration of clarithromycin with buspirone may result in increases in buspirone AUC; the mechanism is probably reduced buspirone metabolism via CYP3A4. A low dose of buspirone is recommended if administered with significant CYP3A4 inhibitors. Subsequent dose adjustments should be based on clinical assessment.
    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.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with clarithromycin if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
    Cabozantinib: (Major) Avoid concomitant use of cabozantinib with clarithromycin due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if clarithromycin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. (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.
    Caffeine; Ergotamine: (Severe) The concurrent use of clarithromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Ergotamine is primarily metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with other strong CYP3A4 inhibitors.
    Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
    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.
    Calcium-channel blockers: (Major) Coadministration of clarithromycin and calcium-channel blockers should be avoided if possible, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. Most reports of acute kidney injury were with the combination of clarithromycin with calcium channel blockers metabolized by CYP3A4 and involved elderly patients at least 65 years of age. Clarithromycin may decrease the clearance of calcium-channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) via inhibition of CYP3A4 metabolism. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). One case of a possible verapamil-clarithromycin interaction was reported, which was associated with hypotension. If the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy, azithromycin is the preferred agent.
    Canagliflozin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Clarithromycin is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control. (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 of drug transporter P glycoprotein (P-gp). Clarithromycin is a P-gp inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control. (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. (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Candesartan; 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.
    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; 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.
    Carbamazepine: (Major) Coadministration of carbamazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Drugs known to inhibit CYP3A4, such as clarithromycin, may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations. Serum carbamazepine concentrations should be monitored closely during coadministration; reduce carbamazepine doses may be necessary. Clarithromycin also inhibits epoxide hydrolase resulting in increased levels of the active metabolite carbamazepine 10, 11- epoxide, which may be more hepatotoxic than the parent drug. Several case reports have documented that clarithromycin can significantly decrease carbamazepine clearance, producing increases in the serum concentration of carbamazepine. Carbamazepine concentrations increased from 12 mcg/ml to 19.1 mcg/ml in a 17-year-old boy after 2 days of clarithromycin 250 mg PO bid. Patients should be monitored for carbamazepine toxicity if clarithromycin is added. Carbamazepine toxicity may be avoided if clarithromycin therapy is begun first and stabilized prior to beginning carbamazepine therapy, however, carbamazepine dosages may need to be increased if clarithromycin is subsequently discontinued. (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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cardiac glycosides: (Major) Clarithromycin has been reported to increase the digoxin AUC by 70% when digoxin is administered orally. No significant changes in digoxin exposure were reported when digoxin was administered intravenously (IV). Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). While this may occur, only 5% of a digoxin dose is subject to metabolism by gut flora and this mechanism does not account for the large increases in digoxin levels that occur with the coadministration of clarithromycin. A more important factor is clarithromycin inhibition of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. Digoxin is a P-gp substrate. Inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. Measure serum digoxin concentrations before initiating clarithromycin. Reduce digoxin concentrations by decreasing the oral digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. No dosage adjustment is required when digoxin is administered IV.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as clarithromycin, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
    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.
    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.
    Ceritinib: (Major) Avoid coadministration of ceritinib with clarithromycin due to increased exposure of both drugs. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of the 150 mg capsules; monitor for treatment-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, further dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After clarithromycin is discontinued, resume the dose of ceritinib taken prior to initiating clarithromycin. Ceritinib is a CYP3A4 substrate and inhibitor; clarithromycin is also a CYP3A4 substrate and a strong CYP3A4 inhibitor. Additionally, ceritinib causes concentration-dependent prolongation of the QT interval, and clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP). (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.
    Cerivastatin: (Major) Macrolide antibiotics such as clarithromycin are not recommended during cerivastatin therapy. There are reports that clarithromycin and other macrolides increase the risk of myopathy and rhabdomyolysis when given with HMG-CoA reductase inhibitors, such as cerivastatin. According to the manufacturer, if no alternative to a short course of clarithromycin therapy is available, brief interruption of cerivastatin should be considered. Clarithromycin potently inhibits CYP3A4. Cerivastatin is metabolized by both CYP2C8 and CYP3A4. When cerivastatin was administered with another potent CYP3A4 inhibitor, the exposure of cerivastatin was increased by approximately 1.5-fold.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Inhibitors of these isoenzymes, such as clarithromycin, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (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) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (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) Concurrent use of chloroquine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). The need to coadminister these drugs should be done with a careful assessment of risks versus benefits. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Chloroquine is also associated with an increased risk of QT prolongation and TdP.
    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; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpromazine: (Major) Concurrent use of chlorpromazine and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both clarithromycin and chlorpromazine are specifically associated with an established risk of QT prolongation and TdP.
    Chlorpropamide: (Moderate) Clarithromycin may enhance the hypoglycemic effects of chlorpropamide. Chlorpropamide is highly protein bound and may be displaced from protein binding sites by other high protein bound drugs, such as clarithromycin, leading to an increase in unbound chlorpropamide concentration and the potential for hypoglycemia. Patients receiving clarithromycin concomitantly with chlorpropamide should be monitored for changes in glycemic control.
    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: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with amiodarone, and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate. Amiodarone is a moderate CYP3A4 inhibitor both in vitro and in vivo. Coadministration with another moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%. (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%.
    Cinacalcet: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. These agents may include clarithromycin. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with ciprofloxacin. Clarithromycin is associated with an established risk for QT prolongation and TdP. Ciprofloxacin has a possible risk for QT prolongation and TdP and should be used cautiously with clarithromycin. (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.
    Cisapride: (Severe) Postmarketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Because of the potential severity of these drug interactions (increased plasma cisapride concentrations and QT prolongation), cisapride use is contraindicated with clarithromycin which inhibits the CYP3A4 isoenzyme.
    Citalopram: (Major) Concurrent use of citalopram and clarithromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If concurrent therapy is considered essential, ECG monitoring is recommended. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Citalopram also causes dose-dependent QT interval prolongation. (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.
    Clindamycin: (Moderate) Concomitant use of clindamycin and clarithromycin may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    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. (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clonazepam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity. (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) CYP3A4 inhibitors may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy. (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: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with clozapine. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. In addition, clarithromycin is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (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: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (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: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (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: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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) 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: (Major) Avoid the concurrent use of cobimetinib with clarithromycin due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; clarithromycin is a P-gp inhibitor and a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). (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.
    Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Guaifenesin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Phenylephrine; Promethazine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with clarithromycin include promethazine. Promethazine carries a possible risk of QT prolongation. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Promethazine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with clarithromycin include promethazine. Promethazine carries a possible risk of QT prolongation. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as clarithromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and clarithromycin in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Clarithromycin can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken clarithromycin in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Severe) Coadministration of conivaptan with strong CYP3A4 inhibitors like clarithromycin is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, another potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and clarithromycin. In addition, conivaptan inhibits CYP3A4; clarithromycin is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. (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.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea, breast tenderness, and endometrial hyperplasia. Patients receiving estrogens should be monitored for an increase in adverse events. In addition, when chronically coadministering clarithromycin (> 30 days) with conjugated estrogens; bazedoxifene, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and clarithromycin if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; clarithromycin is a strong CYP3A inhibitor.
    Crizotinib: (Major) Avoid coadministration of crizotinib with clarithromycin due to increased crizotinib exposure; additive risks of QT prolongation are also possible. Crizotinib is a CYP3A substrate that is associated with concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A inhibitor that has an established risk of QT prolongation and torsade de pointes (TdP). Coadministration of a single dose of crizotinib with another strong CYP3A inhibitor increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    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.
    Cyclobenzaprine: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with cyclobenzaprine. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Cyclobenzaprine has also been associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose.
    Cyclosporine: (Major) Clarithromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Clarithromycin may also reduce the intestinal metabolism of cyclosporine. It has been recommended to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolides concurrently. Increased cyclosporine concentrations may be seen with 2 days of beginning combination therapy. In managing potential interactions between macrolides and cyclosporine, appropriate monitoring of cyclosporine concentrations is critical to help avoid graft failure or drug-related toxicity.
    Cysteamine: (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 clarithromycin, a P-gp inhibitor. Although the coadministration of dabigatran and clarithromycin has no effect on the pharmacokinetics of dabigatran or clarithromycin in healthy subjects, patients should be monitored for increased adverse effects of dabigatran. 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 clarithromycin 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 clarithromycin, 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. (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. (Major) The concomitant use of dabrafenib, a CYP3A4 substrate and moderate CYP3A4 inducer, and clarithromycin, a strong CYP3A4 inhibitor and CYP3A4 substrate, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity and for loss of clarithromycin efficacy.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as clarithromycin. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (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.
    Dapagliflozin; Metformin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Dapagliflozin; Saxagliptin: (Major) The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as clarithromycin.
    Darifenacin: (Moderate) Darifenacin is a substrate of the CYP3A4 isozyme; per the manufacturer, the daily dose of darifenacin should not exceed 7.5 mg when coadministered with potent CYP3A4 inhibitors such as clarithromycin in an effort to minimize increased anticholinergic effects. (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: (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (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: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (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: (Major) Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Moderate) Caution is advised when administering clarithromycin concurrently with dasabuvir. Use of these drugs together may result in elevated concentrations of dasabuvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Dasabuvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with ombitasvir. Use of these drugs together may result in elevated concentrations of ombitasvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Ombitasvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with paritaprevir. Use of these drugs together may result in elevated concentrations of paritaprevir. Clarithromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Paritaprevir is a substrate of CYP3A4 and P-gp. (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) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with dasatinib. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval), and clarithromycin is established to have a causal association with QT prolongation and TdP. Also, clarithromycin is a strong inhibitor of CYP3A4, and dasatinib is metabolized by CYP3A4; concurrent administration of clarithromycin may increase concentrations of dasatinib. It is recommended that an alternative concomitant medication with no or minimal enzyme inhibition potential be selected. If dasatinib must be administered with a strong CYP3A4 inhibitor, a dasatinib dose reduction to 20 mg PO daily should be considered. Also, carefully monitor the patient for dasatinib-related toxicity.
    Daunorubicin: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP) and should be used cautiously with other drugs with a possible risk for QT prolongation and TdP including daunorubicin and doxorubicin. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with clarithromycin. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Since degarelix can cause QT prolongation, degarelix should be used cautiously with other drugs that are associated with QT prolongation. Prescribers need to weigh the potential benefits and risks of degarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with degarelix include clarithromycin.
    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) In a study involving 6 HIV-1-infected patients, coadministration of delavirdine 300 mg 3 times daily with clarithromycin 500 mg twice daily resulted in no significant change in delavirdine pharmacokinetics. However, for patients with renal dysfunction, dosage adjustment of clarithromycin is required during concurrent delavirdine treatment due to decreased clarithromycin elimination. The dose of clarithromycin should be reduced by 50% for patients with a creatinine clearance of 30 to 60 ml/min and for patients with a creatinine clearance of < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
    Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
    Desipramine: (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with clarithromycin, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Dexamethasone: (Major) Coadministration of dexamethasone and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. Additionally, clarithromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of dexamethasone. Increased blood concentrations and physiologic activity may necessitate a decrease in corticosteroid dosage. (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.
    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.
    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; Promethazine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with clarithromycin include promethazine. Promethazine carries a possible risk of QT prolongation.
    Dextromethorphan; Quinidine: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Quinidine (including dextromethorphan; quinidine) and disopyramide are also associated with QT prolongation and TdP. There have been post-marketing reports of TdP occurring with the coadministration of clarithromycin and quinidine or disopyramide. If used concomitantly, monitor ECGs for QT prolongation and consider monitoring serum concentrations of quinidine or disopyramide.
    Diazepam: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as 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.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and penicillins together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including penicillins. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    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. (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.
    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) 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.
    Dienogest; Estradiol valerate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    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. (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Dihydroergotamine: (Severe) Coadministration of clarithromycin with dihydroergotamine is contraindicated due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness). Clarithromycin inhibits dihydroergotamine metabolism via inhibition of the CYP3A4 enzyme.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and clarithromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as clarithromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Disopyramide: (Major) Concurrent administration of clarithromycin and disopyramide has been associated with post-marketing reports of torsades de pointes (TdP) and hypoglycemia. If these drugs are administered together, closely monitor ECGs for QT prolongation, blood glucose concentrations, and consider monitoring disopyramide serum concentrations. Both clarithromycin and disopyramide have been associated with an established risk for QT prolongation and TdP.
    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.
    Docetaxel: (Minor) Docetaxel is partially metabolized by CYP3A4 enzymes. Clarithromycin inhibits the CYP3A4 enzyme and can significantly reduce the metabolism of docetaxel.
    Dofetilide: (Severe) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Because of the potential for TdP, concurrent use is contraindicated.
    Dolasetron: (Severe) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin should be used cautiously with other agents known to cause QT prolongation. Agents with potential to prolong the QT interval include: dolasetron.
    Dolutegravir; 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. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
    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. (Minor) Tricyclic antidepressants should be used cautiously and with close monitoring with clarithromycin. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like clarithromycin, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with 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: (Major) Clarithromycin is a potent inhibitor of CYP3A4, and also inhibits P-glycoprotein (P-gp); doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4 and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Additionally, acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Clarithromycin has a possible risk of causing QT prolongation and torsades de pointes (TdP). Avoid coadministration of clarithromycin and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. (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 clarithromycin 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; clarithromycin is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. (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: (Severe) Concomitant use of dronedarone with clarithromycin is contraindicated. Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. (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.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include clarithromycin.
    Drospirenone; Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Drospirenone; Ethinyl Estradiol: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of clarithromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as clarithromycin, should be avoided.
    Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with clarithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of clarithromycin; monitor for increased adverse effects of 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: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (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: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with clarithromycin should be avoided if possible; consider use of azithromycin in place of clarithromycin. Use of these drugs together is expected to significantly increase the plasma concentration of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Clarithromycin is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, plasma concentrations of clarithromycin (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Eletriptan: (Severe) Eletriptan is contraindicated for use within 72 hours of usage of any drug that is a potent CYP3A4 inhibitor whereby the inhibition effect is described in the prescribing information for the potential interacting drug, such as clarithromycin.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of clarithromycin and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both clarithromycin and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and clarithromycin can independently prolong the QT interval, and coadministration increases this risk. Clarithromycin is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors such as clarithromycin increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. (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: (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.
    Eluxadoline: (Moderate) The effect CYP enzymes have on the metabolism of eluxadoline has not been definitively established; therefore, the manufacturer recommends caution when administering eluxadoline concurrently with strong CYP3A4 inhibitors, such as clarithromycin. When administering these drugs together, closely monitor patients for eluxadoline-related side effects, such as impaired mental and physical abilities need to safely drive or operate machinery.
    Empagliflozin; Linagliptin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    Empagliflozin; Metformin: (Moderate) Clarithromycin may enhance the hypoglycemic effects of antidiabetic agents.
    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. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
    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. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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.
    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 clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (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; 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.
    Enflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with clarithromycin. Halogenated anesthetics can prolong the QT interval and clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP).
    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. (Major) Coadministration of enzalutamide and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction; consider alternatives to clarithromycin if treatment with enzalutamide is necessary. Clarithromycin is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible.
    Epirubicin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with epirubicin. Clarithromycin is associated with an established risk for QT prolongation and TdP. Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eplerenone: (Severe) Coadministration of clarithromycin and eplerenone is contraindicated. Clarithromycin potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Eprosartan; 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.
    Ergonovine: (Severe) The concurrent use of certain macrolides (clarithromycin, erythromycin, and troleandomycin) with ergot alkaloids is thus generally considered contraindicated. The simultaneous use of some ergot alkaloids with troleandomycin has produced ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). The mechanism is related to inhibition of ergot metabolism via CYP3A4.
    Ergotamine: (Severe) The concurrent use of clarithromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Ergotamine is primarily metabolized by CYP3A4, and clarithromycin is a strong inhibitor of CYP3A4. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with other strong CYP3A4 inhibitors.
    Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with eribulin include clarithromycin.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with clarithromycin due to the risk of increased erlotinib-related adverse reactions; if concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Clarithromycin is a strong CYP3A4 inhibitor. Clarithromycin increased the AUC of another CYP3A4 substrate, midazolam, by 174% after IV administration and by 600% after oral administration. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%; coadministration with clarithromycin may also increase erlotinib exposure. (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.
    Erythromycin: (Major) Both clarithromycin and erythromycin are macrolide antibiotics and coadministration would represent duplicate therapy. Additionally, coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation and TdP.
    Erythromycin; Sulfisoxazole: (Major) Both clarithromycin and erythromycin are macrolide antibiotics and coadministration would represent duplicate therapy. Additionally, coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation and TdP. (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as clarithromycin, should be done with caution and close monitoring. In addition, escitalopram is metabolized by CYP3A4. Theoretically, clarithromycin may inhibit this enzyme and lead to elevated plasma levels of this SSRI. However, because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance. (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: (Major) Coadministration of eslicarbazepine and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking CYP3A4 inducers. (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.
    Estazolam: (Moderate) Clarithromycin is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity. (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.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Estradiol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Estradiol; Levonorgestrel: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as clarithromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. Also, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with clarithromycin.
    Estradiol; Norethindrone: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed th