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    Combinations for Treatment of Helicobacter pylori

    DEA CLASS

    Rx

    DESCRIPTION

    Prevpac® contains amoxicillin capsules, clarithromycin tablets, and lansoprazole delayed-release capsules; used for the eradication of H. pylori.

    COMMON BRAND NAMES

    Prevpac

    HOW SUPPLIED

    Amoxicillin Trihydrate;Clarithromycin;Lansoprazole/Amoxicillin;Clarithromycin;Lansoprazole/Prevpac Oral Cap DR Pellets: 500-500-30mg
    Amoxicillin Trihydrate;Clarithromycin;Lansoprazole/Amoxicillin;Clarithromycin;Lansoprazole/Prevpac Oral Cap: 500-500-30mg
    Amoxicillin Trihydrate;Clarithromycin;Lansoprazole/Amoxicillin;Clarithromycin;Lansoprazole/Prevpac Oral Tab: 500-500-30mg

    DOSAGE & INDICATIONS

    For Helicobacter pylori (H. pylori) eradication.
    Oral dosage
    Adults

    1,000 mg amoxicillin PO, 500 mg clarithromycin PO, and 30 mg lansoprazole PO twice daily for 10 days. Guidelines recommend 14 days of treatment and this triple therapy regimen in patients without previous macrolide exposure in regions where clarithromycin resistance is less than 15%.

    MAXIMUM DOSAGE

    Adults

    Amoxicillin 2 g/day PO; clarithromycin 1 g/day PO; lansoprazole 60 mg/day PO.

    Geriatric

    Amoxicillin 2 g/day PO; clarithromycin 1 g/day PO; lansoprazole 60 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

    Dosage or interval adjustments of the clarithromycin component may be necessary in patients with hepatic impairment who also have concomitant significant renal impairment. However, no dosage adjustment is necessary in patients with normal renal function.

    Renal Impairment

    CrCl >= 30 mL/min: no dosage adjustment needed.
    CrCl < 30 mL/min: Prevpac 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, lansoprazole (Prevpac) doses before eating, once in the morning and evening.
    Instruct patients to swallow each pill whole.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Macrolide hypersensitivity

    Prevpac 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

    Prevpac contains amoxicillin, a penicillin, and is contraindicated in patients who have a history of severe hypersensitivity reactions to beta-lactam antibiotic (i.e., penicillin hypersensitivity, 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.

    Proton pump inhibitors (PPIs) hypersensitivity

    Prevpac contains lansoprazole and therefore is contraindicated in patients who have shown lansoprazole hypersensitivity. Lansoprazole 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

    Prevpac (amoxicillin, clarithromycin and lansoprazole in pre-packaged 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 Prevpac (amoxicillin, clarithromycin and lansoprazole in pre-packaged combination) does not preclude the presence of gastric cancer or other malignancy.

    Hepatic disease, hepatitis, jaundice

    Prevpac (amoxicillin, clarithromycin and lansoprazole in pre-packaged combination) should be used with caution in patients with hepatic disease; it is contraindicated in patients with a history of cholestatic jaundice and/or hepatic dysfunction associated with the prior use of the clarithromycin component. Severe, but usually reversible, cases of hepatic dysfunction (i.e., increased liver enzymes, hepatocellular and/or cholestatic hepatitis, jaundice) have been associated with clarithromycin; however, some cases of hepatic failure have resulted in fatal outcomes. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Production of the active metabolite of clarithromycin is reduced in patients with hepatic dysfunction. 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, lansoprazole elimination half-life is significantly prolonged in patients with hepatic disease. Patients with severe hepatic disease might require a lansoprazole dosage adjustment. Abnormal liver-function tests have been reported with lansoprazole use. Hepatic function should be assessed periodically during therapy; discontinue use of the drug immediately is signs/symptoms of hepatitis develop.

    Renal failure, renal impairment

    Prevpac (amoxicillin, clarithromycin and lansoprazole in packaged combination) should be used with caution in patients with renal impairment since both amoxicillin and clarithromycin are eliminated via renal mechanisms. Renal function should be assessed periodically during therapy. Prevpac use is not recommended in patients with renal failure or creatinine clearance (CrCl) less than 30 mL/min since dosages and dosage intervals are not easily adjusted to recommended dosages using the pre-packaged combination.

    Leukemia, mononucleosis, viral infection

    Prevpac contains amoxicillin, clarithromycin and lansoprazole. 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, mortality, myocardial infarction, QT prolongation, thyroid disease, torsade de pointes, ventricular arrhythmias

    Use clarithromycin with caution in patients with cardiac disease, and consider using alternative antibiotics in these patients. 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. 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. 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.

    Bone fractures, osteoporosis

    Use proton pump inhibitors (PPIs) in patients with or who have risk factors for osteoporosis cautiously. PPIs have been associated with a possible increased risk of bone fractures of the hip, wrist, and spine. The risk of fracture was increased in patients who received high-dose (defined as multiple daily doses or doses greater than those recommended in non-prescription use), and long-term PPI therapy (a year or longer); fractures were primarily observed in older adult patients 50 years of age and older. It should be noted that pre-approval randomized clinical trials (RCTs) of PPIs have not found an increased risk of fractures of the hip, wrist, or spine; however, these RCTs were of shorter study duration (generally 6 months or less). When prescribing PPIs, consider whether a lower dose or shorter duration of therapy would adequately treat the patient's condition. In patients with or at risk for osteopenia or osteoporosis, manage their bone status according to current clinical practice, and ensure adequate vitamin D and calcium supplementation.

    Myasthenia gravis

    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 Prevpac combination therapy.

    Pregnancy

    Prevpac contains amoxicillin, clarithromycin, and lansoprazole in a prepackaged combination. Clarithromycin is not recommended for use during pregnancy except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking clarithromycin, advise the patient of the potential risk to the fetus. In a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, clarithromycin use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 2.35; 95% CI: 1.9 to 2.91; 111 exposed cases); residual confounding by severity of infection may be a potential limitation of this study. In another 10-year register-based cohort study in which 401 women were exposed to clarithromycin during the first trimester, 40 women (10%) experienced miscarriage (HR 1.56, 95% CI: 1.14 to 2.13); there was no increased hazard of miscarriage among comparators. In a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, macrolide exposure was associated with an increased risk of digestive system malformations (aOR 1.46; 95% CI: 1.04 to 2.06; 35 exposed cases). In a prospective, multi-center trial (n = 511) of women exposed to macrolides (including clarithromycin) during the first trimester, the rates for major congenital defects were 1.8% for clarithromycin vs. 2.4% in the comparator group (p = 0.8; OR 0.76, 95% CI: 0.25 to 2.27). Other studies of women exposed to a macrolide have not reported major birth defects with clarithromycin. After 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

    Prevpac contains amoxicillin, clarithromycin, and lansoprazole in a prepackaged combination. Discontinue breast-feeding or Prevpac, taking into account the potential risk to the infant vs. the potential benefit to the mother. It is not known whether lansoprazole is excreted into human breast milk; lansoprazole and its metabolites are excreted in the milk of rats.  Due to a paucity of data, lansoprazole and other proton pump inhibitors (PPIs) are generally not recommended for use during lactation. Clarithromycin and its active metabolite are excreted in human milk. No data are available to assess the effects of clarithromycin or its metabolite on milk production. A study in 12 lactating women estimated that infants exclusively breast-fed during maternal consumption of clarithromycin would be exposed at a rate that equates to less than 2% of the maternal weight-adjusted dose and less than 1% of the normal pediatric dose through milk consumption. Another study showed that clarithromycin is transferred to human milk in concentrations that are roughly 25% of maternal serum concentrations. In an observational trial of 55 breast-fed infants of mothers taking a macrolide (6 exposed to clarithromycin), adverse reactions occurred in 12.7% of infants and included rash, diarrhea, loss of appetite, and somnolence. Amoxicillin is excreted in breast milk and may rarely cause diarrhea, candidiasis, and skin rash or other sensitizations in breast-feeding infants; however, previous American Academy of Pediatrics (AAP) recommendations considered amoxicillin use in lactation as low risk.

    Geriatric

    Use caution when prescribing amoxicillin; clarithromycin; lansoprazole in the geriatric patients, as the elimination half-life of lansoprazole is increased, possibly an effect of asymptomatic renal and hepatic dysfunction. Once the initial dosing regimen is complete, a suggested maximum of 30 mg/day of lansoprazole in elderly patients is suggested. Due to known age-related decreases in renal or hepatic function, careful consideration to dose selection for the elderly is advised for clarithromycin and amoxicillin. According to the Beers Criteria, proton pump inhibitors (PPIs) are considered potentially inappropriate medications (PIMs) for use in geriatric patients due to the risk of Clostridium difficile infection and bone loss/fractures. Avoid use for more than 8 weeks except for high-risk patients (e.g., oral corticosteroids or chronic NSAID use), erosive esophagitis, Barrett's esophagitis, pathological hypersecretory condition, or need for maintenance treatment (e.g., due to failure of drug discontinuation trial or inadequate response to H-2 blockers).[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); the indication for PPI use should be based on clinical symptoms and/or endoscopic findings. During the use of PPIs to treat or prevent NSAID-induced gastritis or esophagitis, there should be documentation that analgesics with less GI toxicity than NSAIDs have been tried or were not indicated. If a PPI is used for longer than 12 weeks, the clinical rationale and documentation for continued use should support an underlying chronic disease (e.g., GERD) or risk factors (e.g., chronic NSAID use). Monitor for adverse events, including an increased risk of Clostridium difficile colitis.[60742]

    Children, infants

    Safety and efficacy of Prevpac (amoxicillin, clarithromycin and lansoprazole in pre-packaged combination) in children and infants infected with Helicobacter pylori have not been established.

    Systemic lupus erythematosus (SLE)

    Prevpac contains amoxicillin, clarithromycin and lansoprazole. Use with caution in patients with a history of systemic lupus erythematosus (SLE) as lansoprazole has been reported to activate or exacerbate SLE.

    Laboratory test interference

    Administration of amoxicillin; clarithromycin; lansoprazole may result in laboratory test interference. 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. Preparations that combine PPIs with antimicrobials and bismuth are known to suppress H. pylori; thus, ingestion of these preparations within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of these agents in the 4 weeks prior to the test.

    ADVERSE REACTIONS

    Severe

    esophageal ulceration / Delayed / 0-1.0
    bezoar / Delayed / 0-1.0
    hematemesis / Delayed / 0-1.0
    GI bleeding / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    stroke / Early / 0-1.0
    cardiac arrest / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    atrial fibrillation / Early / 0-1.0
    seizures / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    pancreatitis / Delayed / 0-1.0
    anaphylactic shock / Rapid / 1.0
    anaphylactoid reactions / Rapid / 1.0
    hemolytic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    serum sickness / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    bone fractures / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    glossitis / Early / 0-3.0
    stomatitis / Delayed / 0-3.0
    candidiasis / Delayed / 0-3.0
    vaginitis / Delayed / 0-3.0
    confusion / Early / 0-3.0
    leukopenia / Delayed / 0-1.0
    hemolysis / Early / 0-1.0
    lymphadenopathy / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    anemia / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    oral ulceration / Delayed / 0-1.0
    constipation / Delayed / 1.0-1.0
    dysphagia / Delayed / 0-1.0
    esophagitis / Delayed / 0-1.0
    melena / Delayed / 0-1.0
    cholelithiasis / Delayed / 0-1.0
    gastritis / Delayed / 0-1.0
    chest pain (unspecified) / Early / 0-1.0
    edema / Delayed / 0-1.0
    contact dermatitis / Delayed / 0-1.0
    bullous rash / Early / 0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    dysuria / Early / 0-1.0
    urethral pain / Early / 0-1.0
    urinary retention / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    hypoglycemia / Early / 0-1.0
    dehydration / Delayed / 0-1.0
    gout / Delayed / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    peripheral vasodilation / Rapid / 0-1.0
    migraine / Early / 0-1.0
    palpitations / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    angina / Early / 0-1.0
    hypotension / Rapid / 0-1.0
    hypertension / Early / 0-1.0
    myopathy / Delayed / 0-1.0
    synovitis / Delayed / 0-1.0
    dyskinesia / Delayed / 0-1.0
    hallucinations / Early / 0-1.0
    hypertonia / Delayed / 0-1.0
    depression / Delayed / 0-1.0
    amnesia / Delayed / 0-1.0
    hostility / Early / 0-1.0
    hyperesthesia / Delayed / 0-1.0
    goiter / Delayed / 0-1.0
    diabetes mellitus / Delayed / 0-1.0
    hypothyroidism / Delayed / 0-1.0
    amblyopia / Delayed / 0-1.0
    conjunctivitis / Delayed / 0-1.0
    photophobia / Early / 0-1.0
    blurred vision / Early / 0-1.0
    cataracts / Delayed / 0-1.0
    blepharitis / Early / 0-1.0
    cholestasis / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    bleeding / Early / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    crystalluria / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    dyspnea / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    myasthenia / Delayed / Incidence not known
    mania / Early / Incidence not known
    psychosis / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    diarrhea / Early / 7.0-7.0
    headache / Early / 6.0-6.0
    dysgeusia / Early / 5.0-5.0
    nausea / Early / 0-3.0
    tongue discoloration / Delayed / 0-3.0
    vomiting / Early / 0-3.0
    xerostomia / Early / 0-3.0
    abdominal pain / Early / 0-3.0
    myalgia / Early / 0-3.0
    dizziness / Early / 0-3.0
    anorexia / Delayed / 0-1.0
    flatulence / Early / 0-1.0
    hypersalivation / Early / 0-1.0
    eructation / Early / 0-1.0
    appetite stimulation / Delayed / 0-1.0
    gastroesophageal reflux / Delayed / 0-1.0
    tenesmus / Delayed / 0-1.0
    pelvic pain / Delayed / 0-1.0
    fatigue / Early / 0-1.0
    back pain / Delayed / 0-1.0
    halitosis / Early / 0-1.0
    fever / Early / 0-1.0
    malaise / Early / 0-1.0
    chills / Rapid / 0-1.0
    asthenia / Delayed / 0-1.0
    alopecia / Delayed / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    acne vulgaris / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    xerosis / Delayed / 0-1.0
    leukorrhea / Delayed / 0-1.0
    breast enlargement / Delayed / 0-1.0
    increased urinary frequency / Early / 0-1.0
    menorrhagia / Delayed / 0-1.0
    gynecomastia / Delayed / 0-1.0
    dysmenorrhea / Delayed / 0-1.0
    polyuria / Early / 0-1.0
    urinary urgency / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    weight gain / Delayed / 0-1.0
    syncope / Early / 0-1.0
    tooth discoloration / Delayed / 0-1.0
    ptosis / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    muscle cramps / Delayed / 0-1.0
    agitation / Early / 0-1.0
    anxiety / Delayed / 0-1.0
    diplopia / Early / 0-1.0
    libido decrease / Delayed / 0-1.0
    parosmia / Delayed / 0-1.0
    paresthesias / Delayed / 0-1.0
    drowsiness / Early / 0-1.0
    libido increase / Delayed / 0-1.0
    hyperkinesis / Delayed / 0-1.0
    emotional lability / Early / 0-1.0
    tremor / Early / 0-1.0
    vertigo / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    xerophthalmia / Early / 0-1.0
    ocular pain / Early / 0-1.0
    dyspepsia / Early / 1.0
    rash / Early / 1.0
    insomnia / Early / 1.0
    gastric polyps / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    epistaxis / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    hiccups / Early / Incidence not known
    anosmia / Delayed / Incidence not known
    hyperactivity / Early / Incidence not known

    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) If coadministration with clarithromycin is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If clarithromycin is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of clarithromycin. Abemaciclib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with clarithromycin increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
    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 proton pump inhibitors (PPI), such as lansoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. 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 another PPI for 5 days.
    Acarbose: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    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) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetohexamide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Ado-Trastuzumab emtansine: (Major) Avoid coadministration of clarithromycin with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until clarithromycin has cleared from the circulation (approximately 3 half-lives of clarithromycin) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; clarithromycin is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Afatinib: (Moderate) If the concomitant use of clarithromycin and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of clarithromycin. 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. Afatinib is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor 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 the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Albiglutide: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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: (Severe) Alfuzosin is contraindicated for use with clarithromycin due to the potential for serious/life-threatening reactions, including hypotension. Additive effects on the QT interval may also occur. Alfuzosin is a CYP3A4 substrate that may prolong the QT interval in a dose-dependent manner. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
    Aliskiren; Amlodipine: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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). (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: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with clarithromycin is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and clarithromycin should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
    Alogliptin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Alogliptin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Alogliptin; Pioglitazone: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended. (Moderate) The concomitant use of clarithromycin and oral hypoglycemic agents can result in significant hypoglycemia. With certain hypoglycemic drugs such as the thiazolidinediones, inhibition of CYP3A enzyme by clarithromycin may be involved; however, CYP3A is not a major metabolism route for pioglitazone and rosiglitazone. Careful monitoring of glucose is recommended.
    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) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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%.
    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. (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: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Amlodipine; Atorvastatin: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
    Amlodipine; Benazepril: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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). (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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). (Moderate) Proton pump inhibitors have been associated with hypomagnesemia. Hypomagnesemia occurs with thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). Low serum magnesium may lead to serious adverse events such as muscle spasm, seizures, and arrhythmias. Therefore, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and diuretics concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.
    Amlodipine; Olmesartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Amlodipine; Telmisartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Amlodipine; Valsartan: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Amobarbital: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
    Amphetamine: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Amphetamine; Dextroamphetamine Salts: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Amphetamine; Dextroamphetamine: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    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.
    Apalutamide: (Major) Avoid coadministration of lansoprazole with apalutamide due to decreased lansoprazole exposure. Lansoprazole is a CYP3A4 and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer. (Major) Consider alternatives to clarithromycin if treatment with apalutamide is necessary. Clarithromycin is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer. Inducers of CYP3A enzymes will decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Exposure to apalutamide may also be increased. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively, with this inhibitor. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
    Apixaban: (Moderate) Pharmacokinetic data suggest that no dose adjustment is necessary if apixaban is coadministered with clarithromycin. However, because clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, there is a potential for increased apixaban exposure and increased risk of bleeding with concurrent use of clarithromycin. Monitor patients closely if coadministration is necessary. When combined with other P-gp and strong CYP3A4 inhibitors, the manufacturer recommends reducing the apixaban dose by 50% and avoiding concomitant administration if patients are already receiving 2.5 mg twice daily.
    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 lansoprazole and aprepitant, fosaprepitant are used concurrently and monitor for an increase in lansoprazole-related adverse effects for several days after administration of a multi-day aprepitant regimen. Lansoprazole 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 lansoprazole. 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. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.
    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.
    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: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations. (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: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations. (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: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of 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; Caffeine; Orphenadrine: (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) 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) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4. (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; Citric Acid; Sodium Bicarbonate: (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) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of clarithromycin is necessary. If clarithromycin is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like clarithromycin can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If clarithromycin is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (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) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
    Atorvastatin; Ezetimibe: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
    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) 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) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations. (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.
    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. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and clarithromycin is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    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.
    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: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
    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) 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) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations. (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.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with clarithromycin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of clarithromycin in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    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.
    Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Clarithromycin is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
    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.
    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.
    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.
    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 lansoprazole with boceprevir due to an increased potential for lansoprazole-related adverse events. If lansoprazole 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 lansoprazole. Lansoprazole is a CYP3A4 substrate; boceprevir is a CYP3A4 inhibitor. Coadministration may result in elevated lansoprazole 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. (Minor) Monitor for decreased efficacy of lansoprazole if coadministration with bosentan is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Bosentan is a moderate CYP3A4 inducer. Drugs known to induce CYP3A4 may lead to decreased lansoprazole plasma concentrations.
    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) Concomitant use of bosutinib and lansoprazole resulted 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. Bosutinib displays pH-dependent aqueous solubility. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were decreased by 46% and 26%, respectively, following a single oral dose of bosutinib 400 mg administered after multiple oral doses of lansoprazole 60 mg.
    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; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, 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; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    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: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    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: (Moderate) Monitor for decreased efficacy of lansoprazole if concomitant use of lansoprazole and barbiturates is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Barbiturates induce CYP3A4 and CYP2C19. Drugs known to induce CYP3A4 and CYP2C19 may lead to decreased lansoprazole plasma concentrations.
    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 coadministration of cabozantinib with clarithromycin due to the risk of increased cabozantinib exposure. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets (Cabometyx), reduce the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day); for patients taking cabozantinib capsules (Cometriq), reduce the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 100 mg/day or 100 mg/day to 60 mg/day). Resume the cabozantinib dose that was used prior to initiating treatment with clarithromycin 2 to 3 days after discontinuation of clarithromycin. Cabozantinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased single-dose cabozantinib exposure by 38%.
    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: (Moderate) 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.
    Canagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with clarithromycin. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A4; clarithromycin is a strong inhibitor of CYP3A4. (Moderate) Consider a dose reduction of cannabidiol if coadministered with lansoprazole. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP2C19; lansoprazole is a moderate inhibitor of CYP2C19.
    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) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Carbamazepine induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs. A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If carbamazepine and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    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.
    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 the risk of QT prolongation and increased ceritinib exposure. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; monitor for ceritinib-related adverse reactions. Periodically monitor ECGs and electrolytes; 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 that causes concentration-dependent QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor that is also associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ceritinib exposure by 2.9-fold after a single dose in healthy subjects.
    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.
    Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (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) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    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) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    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 clarithromycin. Monitor for an increase in cilostazol-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%.
    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.
    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 lansoprazole, 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 lansoprazole. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and lansoprazole is an inhibitor of CYP2C19 in vitro. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with clarithromycin. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Clomipramine: (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) Use clarithromycin cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Clarithromycin is a CYP3A4 inhibitor.
    Clorazepate: (Moderate) CYP3A4 inhibitors may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
    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.
    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) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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).
    Codeine: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
    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) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
    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) Concomitant use of codeine with clarithromycin may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Clarithromycin is a strong inhibitor of CYP3A4.
    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.
    Colchicine; Probenecid: (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. (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
    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) Coadministration of lansoprazole and conivaptan may result in increased exposure to lansoprazole. Monitor for increased lansoprazole adverse effects. Lansoprazole is a CYP3A4 substrate and conivaptan is a strong CYP3A4 inhibitor.
    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 clarithromycin with crizotinib due to increased plasma concentrations of crizotinib; additive risks of QT prolongation are also possible. If concomitant use is unavoidable, reduce the dose of crizotinib to 250 mg by mouth once daily and monitor electrolytes and ECGs for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary for QT prolongation. Resume the original crizotinib dose after discontinuation of clarithromycin. 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 with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
    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.
    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.
    Dabrafenib: (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.
    Dacomitinib: (Major) Avoid coadministration of lansoprazole with dacomitinib due to decreased plasma concentrations of dacomitinib which may impact efficacy. Coadministration with another proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Dapagliflozin; Metformin: (Moderate) The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia. Careful monitoring of blood glucose is recommended.
    Dapagliflozin; Saxagliptin: (Major) The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as clarithromycin. The concomitant use of clarithromycin and antidiabetic agents can result in significant hypoglycemia, especially with antidiabetic drugs metabolized via CYP3A4/5. Careful monitoring of blood glucose is recommended.
    Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with clarithromycin due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor.
    Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with clarithromycin is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Clarithromycin is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
    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%.
    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%. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Darunavir; Cobicistat; 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. (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%. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (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) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
    Dasatinib: (Major) Avoid coadministration of dasatinib and clarithromycin due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to clarithromycin with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of clarithromycin in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue clarithromycin or stop dasatinib until clarithromycin is discontinued. Allow a washout of approximately 1 week after clarithromycin is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively. (Major) Do not administer proton pump inhibitors with dasatinib due to the potential for decreased dasatinib exposure and reduced efficacy. Consider using an antacid if acid suppression therapy is needed. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Concurrent use of an proton pump inhibitor reduced the mean Cmax and AUC of dasatinib by 42% and 43%, respectively.
    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. (Minor) Monitor for decreased efficacy of lansoprazole if coadministration with dexamethasone is necessary. Lansoprazole is metabolized by CYP2C19 and CYP3A4. Dexamethasone is a moderate CYP3A4 inducer. Drugs known to induce CYP3A4 may lead to decreased lansoprazole plasma concentrations.
    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) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    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.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and amoxicillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including amoxicillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    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) Lansoprazole 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. Patients with digoxin serum levels at the upper end of the therapeutic range may need to be monitored for potential increases in serum digoxin levels when a PPI is coadministered with digoxin. Finally, PPIs have been associated with hypomagnesemia. Becuase, low serum magnesium may lead to irregular heartbeat and increase the likelihood of serious cardiac arrhythmias, clinicians should monitor serum magnesium concentrations periodically in patients taking a PPI and digoxin concomitantly. Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement. (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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with clarithromycin may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of clarithromycin could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Clarithromycin is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    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.
    Diltiazem: (Major) Avoid coadministration of clarithromycin and diltiazem, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving diltiazem therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor blood pressure and heart rate. Diltiazem is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. 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).
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with clarithromycin may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of clarithromycin could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If clarithromycin is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Clarithromycin is a strong inhibitor of CYP3A4.
    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.
    Docetaxel: (Major) Avoid coadministration of docetaxel with clarithromycin if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
    Dofetilide: (Major) Coadministration of dofetilide and clarithromycin is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP.
    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.
    Doravirine: (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doravirine; Lamivudine; 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. (Minor) Coadministration of doravirine and clarithromycin may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; clarithromycin is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    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: (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.
    Doxorubicin: (Major) Avoid coadministration of clarithromycin with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Clarithromycin is a strong CYP3A4 inhibitor and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 inhibitors or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (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.
    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. Lansoprazole 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: (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; 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