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  • CLASSES

    Antiinfectives for Treatment of Acne
    Macrolide Antibiotics
    Ophthalmological Anti-infectives

    DEA CLASS

    Rx

    DESCRIPTION

    Oral/parenteral/topical macrolide antibiotic. Active against many microbes, but clinical applications are relatively few. Used for Legionnaire's disease and Mycoplasma pneumoniae pneumonia, and as an alternative to beta-lactam antibiotics in allergic patients. May have benefits in hypomotility conditions, such as diabetic gastroparesis.

    COMMON BRAND NAMES

    A/T/S, E.E.S., Emcin Clear, EMGEL, Ery-Tab, ERYC, Erycette, Eryderm, Erygel, Erymax, EryPed, Erythra Derm, Erythrocin Lactobionate, Erythrocin Stearate, Ilotycin, PCE, PCE Dispertab, Romycin, T-Stat

    HOW SUPPLIED

    A/T/S/EMGEL/Erygel/Erythromycin Topical Gel: 2%
    A/T/S/Eryderm/Erymax/Erythra Derm/Erythromycin/T-Stat Topical Sol: 2%
    E.E.S./EryPed/Erythromycin/Erythromycin Ethylsuccinate Oral Gran F/Recon: 5mL, 200mg, 400mg
    E.E.S./Erythrocin Stearate/Erythromycin/Erythromycin Ethylsuccinate Oral Tab: 250mg, 400mg, 500mg
    Emcin Clear/Erycette/Erythromycin Topical Swab: 2%
    ERYC/Erythromycin Oral Cap DR Pellets: 250mg
    Ery-Tab Oral Tab DR: 250mg, 333mg, 500mg
    Erythrocin Lactobionate Intravenous Inj Pwd F/Sol: 1g, 500mg
    Erythromycin/Ilotycin/Romycin Ophthalmic Ointment: 0.5%
    PCE Oral Tab Coated Part: 333mg, 500mg

    DOSAGE & INDICATIONS

    For the treatment of acne vulgaris.
    Oral dosage†
    Adults, Adolescents, and Children 7 years and older

    250 to 500 mg PO twice daily initially, followed by 250 to 500 mg once daily for maintenance. The use of erythromycin for acne has decreased due to the high rates of resistance to P. acnes.

    Topical dosage
    Adults, Adolescents†, and Children 7 years and older†

    Apply a thin layer of a 1.5% or 2% topical preparation (i.e., pledget, solution, gel, or ointment) to the affected area twice daily. Due to a slow onset of action and the increased risk of the development of bacterial resistance, topical antibiotic monotherapy is not recommended. If topical antibiotic therapy is continued longer than a few weeks, the addition of topical benzoyl peroxide is recommended.

    For mild to moderately severe lower respiratory tract infections (e.g., pneumonia, bronchitis) caused by susceptible organisms.
    Oral dosage
    Adults

    250 to 500 mg (of base, estolate or stearate) PO every 6 hours or 400 to 800 mg (ethylsuccinate) PO every 6 hours.

    Infants, Children, and Adolescents

    30 to 50 mg/kg/day (Max: 1 to 2 g/day) PO in 3 to 4 divided doses. 40 mg/kg/day PO in 4 divided doses is recommended by the Infectious Diseases Society of America (IDSA) in pediatric patients with community-acquired pneumonia (CAP) due to presumed/confirmed atypical pathogens as an alternative therapy to azithromycin. The FDA-approved labeling states that up to 100 mg/kg/day (Max: 4 g/day) may be given for more severe infections ; however, this is rarely done in clinical practice.

    Neonates older than 7 days†

    10 mg/kg/dose PO every 8 hours is the general dosing recommended by the American Academy of Pediatrics (AAP).

    Neonates 7 days and younger†

    10 mg/kg/dose PO every 12 hours is the general dosing recommended by the American Academy of Pediatrics (AAP).

    Intravenous dosage
    Adults

    15 to 20 mg/kg/day IV given in divided doses every 6 hours (Max: 4 g/day). The FDA-approved labeling states that continuous infusion of erythromycin is preferred ; however, this is not commonly done in clinical practice.

    Infants, Children, and Adolescents

    15 to 20 mg/kg/day (Max: 2 to 4 g/day) IV divided every 6 hours. The Infectious Diseases Society of America (IDSA) recommends 20 mg/kg/day IV divided every 6 hours in children with community-acquired pneumonia due to presumed/confirmed atypical pathogens as an alternative therapy to azithromycin. The FDA-approved labeling states that continuous infusion of erythromycin is preferred ; however, this is not commonly done in clinical practice.

    Neonates older than 7 days†

    10 mg/kg/dose IV every 8 hours is the general dosing recommended by the American Academy of Pediatrics (AAP). Higher doses (40 mg/kg/day IV divided every 6 hours) have been reported as effective and well tolerated in premature neonates (n = 14; gestational age, 23 to 29 weeks; postnatal age, 2 to 15 days) for Ureaplasma urealyticum pneumonia.

    Neonates 7 days and younger†

    10 mg/kg/dose IV every 12 hours is the general dosing recommended by the American Academy of Pediatrics (AAP). Higher doses (40 mg/kg/day IV divided every 6 hours) have been reported as effective and well tolerated in premature neonates (n = 14; gestational age, 23 to 29 weeks; postnatal age, 2 to 15 days) for Ureaplasma urealyticum pneumonia.

    For the treatment of Legionnaire's disease (caused by Legionella pneumophila).
    Oral dosage
    Adults

    0.5 g to 1 g PO every 6 hours for 21 days.

    Intravenous dosage
    Adults

    0.5 to 1 g IV every 6 hours for 21 days. Although other treatments exist, IV erythromycin is still a standard therapy. In 1 retrospective analysis (n = 104) there was a trend towards improved survival in hospitalized patients treated with erythromycin IV (p = 0.063) vs. those treated with other antibiotics; erythromycin-related side-effects such as phlebitis were common.

    For the treatment of mild to moderately severe upper respiratory tract infections (e.g., pharyngitis, tonsillitis), including group A beta-hemolytic streptococcal (GAS) pharyngitis (primary rheumatic fever prophylaxis).
    For upper respiratory tract infections and GAS pharyngitis (primary rheumatic fever prophylaxis).
    Oral dosage
    Adults

    250 to 500 mg (of base, estolate, or stearate) PO every 6 hours or 400 to 800 mg (ethylsuccinate) PO every 6 hours for 10 days. The manufacturers and the American Heart Association (AHA) recommend erythromycin as an alternative to penicillin.

    Infants, Children, and Adolescents

    30 to 50 mg/kg/day PO in 3 to 4 divided doses for 10 days (Max: 1 to 2 g/day). The FDA-approved labeling states that up to 100 mg/kg/day (Max: 4 g/day) may be given for more severe infections ; however, this is rarely done in clinical practice. For the treatment of group A streptococcal pharyngitis, the American Heart Association (AHA) and the Infectious Diseases Society of America (IDSA) recommend erythromycin as an alternative for patients allergic to penicillin.

    For prevention of recurrent attacks of rheumatic fever (i.e., secondary rheumatic fever prophylaxis).
    Oral dosage
    Adults, Adolescents, and Children

    A macrolide, such as erythromycin, is recommended for secondary prevention of rheumatic fever in patients allergic to both penicillin and sulfisoxazole; however, dosing recommendations are not provided in recent guidelines by the American Heart Association (AHA). Previous guidelines stated that dosing is not well established and suggested an erythromycin dose of 250 mg PO twice daily. The AHA recommends secondary prophylaxis for 10 years or until age 40 (whichever is longer) for patients who have experienced rheumatic fever with carditis and have residual heart disease (persistent valvular disease). For patients who have experienced rheumatic fever with carditis, but have no residual heart disease, the AHA recommends prophylaxis for 10 years or until age 21 (whichever is longer). For patients who have experienced rheumatic fever without carditis, the AHA recommends prophylaxis for 5 years or until age 21 (whichever is longer).

    For the treatment of listeriosis.
    Oral dosage
    Adults

    250 to 500 mg (of base, estolate or stearate) PO every 6 hours or 400 to 800 mg (ethylsuccinate) PO every 6 hours.

    Infants, Children, and Adolescents

    30 to 50 mg/kg/day (Max: 1 to 2 g/day) PO in 3 to 4 divided doses. The FDA-approved labeling states that up to 100 mg/kg/day (Max: 4 g/day) may be given for more severe infections ; however, this is rarely done in clinical practice.

    For the treatment of chlamydia infection and non-gonococcal urethritis.
    For the treatment of non-gonococcal urethritis (NGU) or chlamydial infections including urogenital infections (urethritis, cervicitis, proctitis) and infant pneumonia.
    Oral dosage (erythromycin ethylsuccinate, base, or stearate)
    Adults and Adolescents†

    As an alternative to azithromycin or doxycycline, the CDC recommends erythromycin base 500 mg PO or erythromycin ethylsuccinate 800 mg PO 4 times daily for 7 days. In pregnant patients, the CDC recommends additional regimens of erythromycin base 250 mg PO or erythromycin 400 mg PO 4 times daily for 14 days as an alternative to azithromycin or amoxicillin in chlamydial infections. Erythromycin stearate is also approved for use at a dose of 500 mg PO 4 times daily or 666 mg PO every 8 hours for 7 days. For pregnant women who cannot tolerate these doses, 500 mg PO every 12 hours, 333 mg PO every 8 hours, or 250 mg PO 4 times daily for 14 days is recommended. Erythromycin base is also approved for proctitis; however, the CDC does not recommend erythromycin for proctitis.

    Children 8 years and older or weighing 45 kg or more†

    Erythromycin is not recommended. The Centers for Disease Control (CDC) recommends single-dose azithromycin. Doxycycline may also be used in children 8 years and older.

    Infants† and Children younger than 8 years and weighing less than 45 kg†

    50 mg/kg/day (base or ethylsuccinate; Max: 2 g/day) PO in 4 divided doses for 14 days. Monitor for infantile hypertrophic pyloric stenosis (IHPS) in infants less than 6 weeks old.

    For the treatment of chlamydial conjunctivitis or ophthalmia neonatorum caused by Chlamydia trachomatis.
    Oral dosage (base or ethylsuccinate)
    Neonates

    The CDC recommends 50 mg/kg/day PO divided into 4 daily doses for 14 days. A second course may be required. The CDC states that topical therapy alone is inadequate and in unnecessary when systemic therapy is administered.

    For the treatment of lymphogranuloma venereum† caused by Chlamydia trachomatis.
    Oral dosage (erythromycin base)
    Adults and Adolescents

    The CDC recommends 500 mg PO 4 times per day for 21 days as an alternative to the first-line agent doxycycline. Erythromycin is considered first-line therapy in pregnant and lactating women.

    For the prevention of ophthalmia neonatorum (i.e., ophthalmia neonatorum prophylaxis) due to Neisseria gonorrhoeae or Chlamydia trachomatis.
    Ophthalmic dosage
    Neonates

    Apply a ribbon of 0.5% ophthalmic ointment into each lower conjunctival sac no later than 1 hour after birth. Do not flush eyes after instillation. Use a new tube for each infant.

    For the treatment of pneumonia caused by Chlamydia trachomatis in neonates and infants.
    Oral dosage (base or ethylsuccinate)
    Neonates and Infants

    50 mg/kg/day (base or ethylsuccinate) PO in 4 divided doses. The Centers for Disease Control (CDC) recommends a treatment course of 14 days; a second course may be required. Some manufacturers recommend treatment for at least 3 weeks. Monitor for infantile hypertrophic pyloric stenosis (IHPS) in infants less than 6 weeks old.

    For the adjunctive treatment of diphtheria to prevent establishment of carrier state and for Corynebacterium diphtheriae bacterial colonization eradication.
    For the treatment of close contacts of patients with diphtheria (i.e., diphtheria prophylaxis†).
    Oral dosage
    Adults

    250 mg PO every 6 hours for 7 to 10 days.

    Infants, Children, and Adolescents

    40 mg/kg/day (Max: 1 g/day) PO in 3 to 4 divided doses for 7 to 10 days.

    Oral dosage
    Adults

    500 mg PO every 6 hours for 14 days.

    Infants, Children, and Adolescents

    40 mg/kg/day (Max: 2 g/day) PO in 3 to 4 divided doses for 14 days.

    Intravenous dosage
    Adults, Adolescents, Children, and Infants

    40 mg/kg/day (Max: 2 g/day) IV divided every 6 to 12 hours for 14 days. The FDA-approved dosing is 15 to 20 mg/kg/day (up to 4 g/day for severe infections) IV divided every 6 hours.

    For the treatment of acute pelvic inflammatory disease (PID).
    For acute pelvic inflammatory disease (PID) caused by Neisseria gonorrhoeae.
    Intravenous and Oral dosage
    Adults

    Due to resistance, the CDC does not recommend erythromycin. The manufacturer recommends 500 mg IV every 6 hours for 3 days, then 250 mg erythromycin base or stearate or 400 mg erythromycin ethylsuccinate PO every 6 hours for 7 days.

    For the treatment of pertussis (whooping cough) caused by Bordetella pertussis or for postexposure pertussis prophylaxis.
    NOTE: For postexposure prophylaxis, administer to close contacts within 3 weeks of exposure, especially in high-risk patients (e.g., women in third trimester, infants < 12 months).
    Oral dosage
    Adults

    500 mg PO 4 times per day (2 g total) for 14 days.

    Infants, Children, and Adolescents

    40—50 mg/kg/day PO (maximum 2 g/day) in 4 divided doses for 14 days.

    Neonates

    Azithromycin is the preferred agent. If azithromycin unavailable, erythromycin 40—50 mg/kg/day PO in 4 divided doses may be used. Monitor for infantile hypertrophic pyloric stenosis (IHPS) (see Adverse Reactions).

    For the treatment of primary syphilis (caused by Treponema pallidum) in penicillin-allergic, nonpregnant patients.
    Oral dosage (erythromycin ethylsuccinate, base, or stearate)
    Adults

    48—64 g PO of erythromycin ethylsuccinate or 30—40 g PO of erythromycin base or erythromycin stearate given in divided doses over a period of 10—15 days. Erythromycin is not included in the CDC's sexually transmitted diseases guidelines for syphilis.

    For bowel preparation in combination with neomycin in patients undergoing colorectal surgery.
    Oral dosage
    Adults

    1 g PO in combination with neomycin 1 g PO. Give as 3 doses over 10 hours the day before surgery (i.e., 1 pm, 2 pm, and 11 pm on the day before 8 am surgery). Appropriate IV antibmicrobial prophylaxis should also be given.

    Infants†, Children†, and Adolescents†

    20 mg/kg/dose (Max: 1 g/dose) PO in combination with neomycin 15 mg/kg/dose (Max: 1 g/dose) PO. Give as 3 doses over 10 hours the day before surgery (i.e., 1 pm, 2 pm, and 11 pm on the day before 8 am surgery). Appropriate IV antibmicrobial prophylaxis should also be given. Data for antimicrobial prophylaxis in colorectal surgery in pediatric patients are lacking; however, it is suggested that prophylactic regimens that have been studied in adults would have similar efficacy in children.

    For the treatment of superficial ophthalmic infection involving the conjunctiva and/or cornea.
    Ophthalmic dosage
    Adults, Adolescents, Children, and Infants

    Apply a ribbon approximately 1 cm in length to the infected structure of the eye up to 6 times daily, depending on severity of infection.

    For the treatment of chancroid† due to Haemophilus ducreyi.
    Oral dosage (erythromycin base)
    Adults, Adolescents, and Children 45 kg or greater

    500 mg PO 3 times daily for 7 days is recommended as an alternative to single-dose azithromycin. Complicated or severe infections may require prolonged therapy. A longer course of therapy may be required in HIV-infected patients and uncircumcised males. Worldwide, isolates with intermediate resistance have been reported; however, data are limited regarding prevalence.

    Infants and Children less than 45 kg

    Erythromycin dosing recommendations are not available in children. If oral treatment is chosen, single-dose azithromycin is the preferred therapy recommended by the American Academy of Pediatrics (AAP).

    For the treatment of disseminated gonorrhea†.
    NOTE: Erythromycin is not recommended in adults, adolescents, or children 8 years and older or in patients weighing 45 kg or more due to resistance of N. gonorrheae against erythromycin in the United States. Single-dose azithromycin in combination with ceftriaxone is the preferred therapy in these populations.
    Oral dosage (base or ethylsuccinate)
    Infants and Children younger than 8 years and weighing less than 45 kg

    50 mg/kg/day (base or ethylsuccinate; Max: 2 g/day) PO in 4 divided doses for 14 days in combination with ceftriaxone.

    For the facilitation of gastric emptying in patients with delayed gastrointestinal motility (e.g., gastroparesis†).
    For the treatment of idiopathic or postsurgical gastroparesis† or diabetic gastroparesis†.
    Oral dosage
    Adults

    250 to 500 mg PO 3 times daily, 30 minutes before meals, is recommend in treatment guidelines for a short course of therapy in patients with persistent symptoms following trials of standard prokinetic therapy (e.g., metoclopramide). A systematic review of studies showed a 43% improvement of symptoms with oral erythromycin. The oral suspension is often utilized due to rapid absorption and to facilitate dose modifications. Although dosage can be titrated to effect, side effects often limit the dose tolerated for gastroparesis. The effectiveness of chronic therapy may be limited due to the development of tachyphylaxis as a result of motilin receptor downregulation. Clinical responsiveness to oral erythromycin declines after 4 weeks.

    Infants, Children, and Adolescents

    3 mg/kg/dose PO 4 times daily; up to 10 mg/kg/dose (Max: 250 mg/dose) PO 4 times daily has been used; however, data are limited. Guidelines for the treatment of gastroparesis state that oral erythromycin improves gastric emptying; however, long-term use (e.g., more than 4 weeks) is limited by tachyphylaxis.

    Intravenous dosage
    Adults

    3 mg/kg IV every 8 hours, infused over 45 min to avoid sclerosing veins, has been studied in hospitalized patients with diabetic gastroparesis and is the dosage recommended in gastroparesis treatment guidelines. Although dosage can be titrated to effect, side effects often limit the dosage tolerated for gastroparesis. The effectiveness of chronic therapy may be limited due to the development of tachyphylaxis as a result of motilin receptor downregulation.

    Infants, Children, and Adolescents

    3 mg/kg/dose (Max: 250 mg/dose) IV every 6 to 8 hours; however, data are limited in children. 3 mg/kg/dose every 8 hours is recommended by clinical guidelines if an IV prokinetic agent is needed. However, metoclopramide is considered the first-line agent.

    For the facilitation of gastric emptying† in patients with feeding intolerance†.
    Intravenous dosage
    Adults

    Doses of 70 or 200 mg IV as single dose, 200 mg IV every 12 hours for 7 days, or 250 mg IV every 6 hours for at least 24 to 48 hours have been used. In placebo-controlled studies that evaluated single doses of erythromycin (70 mg or 200 mg IV), patients treated with erythromycin demonstrated statistically significantly improved gastric emptying volumes and half-emptying volumes , had increased frequency and amplitude of gastric antrum contractions , and had a higher gastric emptying coefficient (GEC) as compared to placebo . In another placebo-controlled trial, trauma patients treated with erythromycin 250 mg IV every 6 hours reached a higher percentage of target enteral nutrition volume at 48 hours compared to those that received placebo (58% vs. 44%, p = 0.011); however, there was no difference in the amount of feeding tolerated over the course of the entire study. In 2 studies comparing erythromycin (250 mg IV every 6 hours or 200 mg IV every 12 hours) to metoclopramide (10 mg IV every 6 hours), gastric residual volumes were reduced and feeding rates increased similarly in both patient groups. However, another study showed that erythromycin 200 mg IV every 12 hours provided a greater percentage of gastric residual volume reduction (59 +/- 4% vs. 35 +/- 6%, p < 0.001), and the percentage of patients successfully fed with enteral nutrition was higher with erythromycin as compared to metoclopramide (87% vs. 62%, p = 0.02).

    Infants, Children, and Adolescents

    3 mg/kg/dose (Max: 250 mg/dose) IV every 6 to 8 hours; however, data are limited in children. 3 mg/kg/dose every 8 hours is recommended by clinical guidelines if an IV prokinetic agent is needed. However, metoclopramide is considered the first-line agent.

    Oral dosage
    Infants, Children, and Adolescents

    3 mg/kg/dose PO 4 times daily; up to 10 mg/kg/dose (Max: 250 mg/dose) PO 4 times daily has been used; however, data are limited. Guidelines for the treatment of gastroparesis state that oral erythromycin improves gastric emptying; however, long-term use (e.g., more than 4 weeks) is limited by tachyphylaxis.

    Neonates

    10 to 12.5 mg/kg/dose PO every 6 hours given 30 minutes before feedings; however optimal dose has not been established and efficacy outcomes have differed in various studies. Most studies have used a treatment duration of 10 to 14 days. Studies of erythromycin for 'rescue therapy' (treatment of gastrointestinal dysmotility) in neonates (mainly premature neonates) have shown that high-dose erythromycin (50 mg/kg/day) is necessary to achieve significant prokinetic effects from erythromycin. In clinical studies, high-dose erythromycin has improved feeding tolerance, shortened the time that parenteral nutrition is required, and decreased the incidence of parenteral nutrition-associated cholestasis. Prophylactic therapy with erythromycin has not shown clinical efficacy in most studies. Intermediate-dose erythromycin (20 mg/kg/day PO divided every 6 hours) was also shown to improve feeding tolerance, and shorten parenteral nutrition duration and time to achieve body weight of 2500 g or more compared with placebo in a study of 45 very low birthweight infants. Low-dose erythromycin (less than 15 mg/kg/day) has been used in studies, but conflicting results have been reported. Some studies have shown a benefit while others have not. There have also been conflicting results with regards to efficacy for gestational age (GA) in studies that stratified results by GA. Some studies have only seen benefit in neonates older than 32 weeks , while others have reported benefit only in infants younger than 32 weeks.

    For the treatment of early Lyme disease†.
    Oral dosage
    Adults

    500 mg PO 4 times per day for 14 to 21 days. Macrolides are not recommended as first-line agents for early Lyme disease and are only recommended for patients who are intolerant of, or are unable to take amoxicillin, doxycycline, or cefuroxime.

    Infants, Children, and Adolescents

    50 mg/kg/day (Max: 2 g/day) PO in 4 divided doses for 14 to 21 days. Macrolides are not recommended as first-line agents for early Lyme disease and are only recommended for patients who are intolerant of, or are unable to take amoxicillin, doxycycline, or cefuroxime.

    For the treatment of skin and skin structure infections including impetigo and burn wound infection†.
    For the treatment of erythrasma (caused by Corynebacterium minutissimum).
    Oral dosage
    Adults

    250 mg PO 3 times per day for 21 days.

    Oral dosage
    Adults

    250 to 500 mg (of base, estolate, or stearate) PO every 6 hours or 400 to 800 mg (ethylsuccinate) PO every 6 hours.

    Infants, Children, and Adolescents

    30 to 50 mg/kg/day (Max: 2 g/day) PO in 3 to 4 divided doses. The FDA-approved labeling states that up to 100 mg/kg/day (Max: 4 g/day) may be given for more severe infections ; however, this is rarely done in clinical practice.

    Neonates older than 7 days†

    10 mg/kg/dose PO every 8 hours is the general dosing recommended by the American Academy of Pediatrics (AAP).

    Neonates 7 days and younger†

    10 mg/kg/dose PO every 12 hours is the general dosing recommended by the American Academy of Pediatrics (AAP).

    Intravenous dosage
    Adults, Adolescents, Children, and Infants

    15 to 20 mg/kg/day (Max: 4 g/day) IV divided every 6 hours. The FDA-approved labeling states that continuous infusion of erythromycin is preferred; however, this is not commonly done in clinical practice.

    Neonates older than 7 days†

    10 mg/kg/dose IV every 8 hours is the general dosing recommended by the American Academy of Pediatrics (AAP).

    Neonates 7 days and younger†

    10 mg/kg/dose IV every 12 hours is the general dosing recommended by the American Academy of Pediatrics (AAP).

    For the treatment of tetanus† (caused by Clostridium tetani) when penicillin or tetracycline is contraindicated or not tolerated.
    Oral dosage
    Adults

    500 mg PO every 6 hours for 10 days has been used.

    For the treatment of granuloma inguinale† (Donovanosis) caused by Klebsiella granulomatis.
    Oral dosage (erythromycin base)
    Adults and Adolescents

    As an alternative, the CDC recommends 500 mg PO 4 times daily for a minimum of 3 weeks and until all lesions have completely healed. The addition of an aminoglycoside, such as gentamicin, should be considered if lesions do not respond within the first few days of therapy or if the patient also has HIV infection. Erythromycin is recommended by the CDC for pregnant and lactating patients.

    For the treatment of cholera†.
    Oral dosage
    Adults

    250 mg PO every 6 hours for 3 days (12 doses total) in conjunction with fluid and electrolyte replacement.

    Infants, Children, and Adolescents

    12.5 mg/kg/dose (Max: 250 mg/dose) PO every 6 hours for 3 days (12 doses total) in conjunction with fluid and electrolyte replacement.

    For the treatment of bartonellosis† (Bartonella bacilliformis) and other Bartonella sp.† infections in HIV-infected patients.
    For the treatment of angiomatosis infections†, peliosis hepatis†, bacteremia†, and osteomyelitis† caused by Bartonella sp.†.
    Intravenous and Oral dosage
    Adults and Adolescents

    500 mg PO or IV 4 times daily for at least 3 months is recommended by the HIV guidelines. Rifampin may be added for other severe infections. Severe Jarisch-Herxheimer-like reactions can occur during the first 48 hours of therapy.

    For long term suppression† of infections caused by Bartonella sp.† in HIV-infected patients with relapse or reinfections with < 200 CD4 cells/mm3.
    Oral dosage
    Adults and Adolescents

    500 mg PO 4 times daily is recommended by the HIV guidelines. Discontinuation of suppressive therapy may be considered after 3—4 months of treatment and > 200 CD4 cells/mm3 for at least 6 months. Some experts suggest that Bartonella titers also decrease by 4-fold prior to discontinuation of suppressive therapy.

    For pneumococcal prophylaxis† in penicillin-allergic patients with sickle cell disease†.
    Oral dosage
    Infants and Children

    10 mg/kg/dose PO twice daily. A maximum dose has not been defined, but one protocol used doses of 125 mg PO twice daily for infants and children 4 months to 3 years of age and 250 mg PO twice daily for children 3 to 4 years of age. The American Academy of Pediatrics (AAP) recommends erythromycin as an alternative for children with penicillin allergy; however, it does not provide dosing recommendations. Prophylaxis is recommended to be initiated by 2 months of age and continued until the fifth birthday. For children more than 5 years, the National Institutes of Health recommends giving parents the option to continue prophylaxis if desired.

    For the treatment of infantile acne†.
    For the oral treatment of infantile acne.
    Oral dosage
    Infants and Children younger than 2 years

    125 to 375 mg PO twice daily (approximately 30 to 40 mg/kg/day PO in 2 divided doses). 125 mg PO twice daily was successfully used in patients with moderate acne (n = 18) in a case series of 29 infants and children 6 to 16 months of age with infantile acne. Higher doses (250 or 375 mg twice daily) were necessary in patients with severe acne.

    For the topical treatment of infantile acne.
    Topical dosage
    Infants and Children younger than 2 years

    Apply a thin layer of a 2% topical preparation to the affected area twice daily. Due to a slow onset of action and the increased risk of the development of bacterial resistance, topical antibiotic monotherapy is not recommended. If topical antibiotic therapy is continued longer than a few weeks, the addition of topical benzoyl peroxide is recommended.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4 g erythromycin base/day PO; 4 g/day IV.

    Geriatric

    4 g erythromycin base/day PO; 4 g/day IV.

    Adolescents

    50 mg/kg/day (Max: 2 g/day) PO is the common maximum dose used in clinical practice; however, up to 100 mg/kg/day PO (Max: 4 g/day) is FDA-approved for the treatment of severe infections. 20 mg/kg/day (Max: 4 g/day) is the FDA-approved IV maximum dose; however, doses up to 40 mg/kg/day (Max: 4 g/day) IV have been used off-label.

    Children

    50 mg/kg/day (Max: 2 g/day) PO is the common maximum dose used in clinical practice; however, up to 100 mg/kg/day PO (Max: 4 g/day) is FDA-approved for the treatment of severe infections. 20 mg/kg/day (Max: 4 g/day) is the FDA-approved IV maximum dose; however, doses up to 40 mg/kg/day (Max: 4 g/day) IV have been used off-label.

    Infants

    50 mg/kg/day PO is the common maximum dose used in clinical practice; however, up to 100 mg/kg/day PO is FDA-approved for the treatment of severe infections. 20 mg/kg/day is the FDA-approved maximum IV dose; however, doses up to 40 mg/kg/day IV have been used off-label.

    Neonates

    50 mg/kg/day PO; safety and efficacy of IV use have not been established, however, doses up to 40 mg/kg/day IV have been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Erythromycin should be used with caution in patients with impaired hepatic function. Although specific dosage guidelines are not available, a reduced dosage may be necessary.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    Oral Administration

    Most formulations are well absorbed and can be given without regard to meals. However, optimal absorption is achieved in the fasting state (1/2 hour before meals or 2 hours after meals). If GI irritation occurs, may be administered with food.

    Oral Solid Formulations

    Erythromycin ethylsuccinate film-coated tablets: Swallow whole; do not crush, break, or chew. May be administered without regard to meals.
    Erythromycin stearate: Swallow whole; do not crush, break, or chew. Administer in the fasting state or immediately prior to meals.
    Erythromycin base, delayed-release tablets or capsules (enteric coated): Swallow whole; do not crush, chew, or open. May be given without regard to meals.

    Oral Liquid Formulations

    Erythromycin ethylsuccinate suspension: FDA-approved labeling states that may be given without regard to meals ; however, studies have shown better absorption when given with milk or food.
    Shake well before administration. Administer using a calibrated measuring device.

    Extemporaneous Compounding-Oral

    Reconstitution
    Review the manufacturer’s reconstitution instructions for the particular product and package size; the amount of water to be used for reconstitution may vary between manufacturers.
    Prior to constitution, tap the bottle several times to loosen the powder.
    Add approximately half of the total amount of water needed and shake well. Add the remaining water and shake well. Resultant concentration will be 40 or 80 mg/mL.
    Storage: The prepared oral suspension should be refrigerated and used within 10 days.

    Injectable Administration

    Do not administer intramuscularly (IM).
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution
    Vials: Reconstitute each 500 mg vial with 10 ml of Sterile Water for Injection for a resultant concentration of 50 mg/mL. Other diluents may cause precipitation during reconstitution. Do not use diluents containing preservatives or inorganic salts.
    Storage: Reconstituted solutions are stable for 24 hours at room temperature or 14 days under refrigeration.
    ADD-Vantage vials: Reconstitute only in 100 ml flexible container with 0.9% NaCl (NS) or 5% Dextrose.
    Storage: ADD-Vantage vials should be reconstituted immediately before administration. However, if not, the diluted solution should be completely administered within 8 hours when reconstituted in 0.9% Sodium Chloride injection and 2 hours when reconstituted in 5% Dextrose injection.
    Dilution of vials
    Dilute appropriate dose in 0.9% Sodium Chloride injection or Lactated Ringer's to a final concentration of 1—5 mg/mL.
    If 5% Dextrose injection or solution containing 5% Dextrose injection, Dextrose 5% and Lactated Ringer's (D5LR) or Dextrose 5% and Sodium Chloride 0.9% (D5NS), is necessary as a diluent, it must be first buffered with 1 mL of Neut (4% sodium bicarbonate, Hospira) per 100 mL of solution.
    For continuous infusion, the manufacturer recommends a concentration of 1 mg/mL; however, continuous infusion is rarely utilized in clinical practice.
    Storage: The final diluted solution should be completely administered within 8 hours.
     
    Intermittent IV Infusion
    Administer IV over 20—60 minutes.
    Assess for injection site reactions during infusion.
     
    Continuous IV infusion:
    Dilute 1 gram in 1 liter of 0.9% Sodium Chloride injection, Lactated Ringer's, or Normosol-R. The following solutions may also be used if they are first buffered with Neut (sodium bicarbonate 4%, Abbott) by adding 1 mL of Neut per 100 mL solution: Dextrose 5% (D5W), Dextrose 5% and Lactated Ringer's (D5LR), and Dextrose 5% and Sodium Chloride 0.9% (D5NS). Infuse IV over 4 hours.

    Topical Administration

    Do not use topical preparations near the eyes, nose, mouth, or other mucous membranes.
    Cleanse and pat dry the affected area prior to application. Gloves should be worn during application.

    Cream/Ointment/Lotion Formulations

    Ointment: Apply a thin film to the cleansed affected area as prescribed.

    Other Topical Formulations

    Gel and Solution:
    Apply a thin film to the cleansed affected area as prescribed.
     
    Saturated erythromycin pledgets:
    Apply solution to cleansed affected area by gently rubbing pledgets over affected skin. Several pledgets may be required per application.

    Ophthalmic Administration

    Apply topically to the eye taking care to avoid contamination. For ophthalmic use only.
    Instruct patient on proper instillation of eye ointment.
    Do not to touch the tip of the tube to the eye, fingertips, or other surface.

    STORAGE

    Generic:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from moisture
    - Store below 86 degrees F
    A/T/S:
    - Flammable, keep away from heat and flame
    - Store and dispense in original container
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Akne-mycin:
    - Store below 80 degrees F
    E.E.S.:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store reconstituted product in refrigerator (36 to 46 degrees F), discard after 10 days
    Emcin Clear :
    - Store at room temperature (between 59 to 86 degrees F)
    EMGEL:
    - Flammable, keep away from heat and flame
    - Store and dispense in original container
    - Store at controlled room temperature (between 68 and 77 degrees F)
    ERYC:
    - Store at room temperature (between 59 to 86 degrees F)
    Erycette:
    - Store at room temperature (between 59 to 86 degrees F)
    Eryderm :
    - Store between 59 to 77 degrees F
    - Store in a dry place
    Erygel:
    - Flammable, keep away from heat and flame
    - Store and dispense in original container
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Erymax:
    - Store between 59 to 77 degrees F
    - Store in a dry place
    EryPed:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store reconstituted product in refrigerator (36 to 46 degrees F), discard after 10 days
    Ery-Tab:
    - Store below 86 degrees F
    Erythra Derm :
    - Store between 59 to 77 degrees F
    - Store in a dry place
    Erythrocin Lactobionate:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Erythrocin Stearate:
    - Store below 86 degrees F
    Ilotycin:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    PCE:
    - Store below 86 degrees F
    PCE Dispertab :
    - Store below 86 degrees F
    Romycin:
    - Avoid excessive heat (above 104 degrees F)
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    T-Stat:
    - Store between 59 to 77 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Antibiotic therapy can result in superinfection or suprainfection with non susceptible organisms. Overgrowth of Candida can occur with erythromycin therapy. Patients should be monitored closely during therapy.

    Viral infection

    Erythromycin does not treat viral infection (e.g., common cold). Prescribing erythromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients should be told to complete the full course of treatment, even if they feel better earlier.

    Macrolide hypersensitivity

    Patients who have shown macrolide hypersensitivity or sensitivity to any macrolide antibiotic should not be given erythromycin. Erythromycin can cause rare, but serious allergic reactions, including angioedema and anaphylaxis. There is a risk of cross sensitivity with other macrolide antibiotics.

    Hepatic disease

    Erythromycin is excreted mainly by the liver. Patients with impaired hepatic or biliary function should receive erythromycin with caution. Hepatic function should be monitored in patients receiving prolonged treatment with erythromycin. The estolate salt of erythromycin should not be used in patients with hepatic disease because of the potential for hepatotoxicity.

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

    Almost all antibacterial agents, including erythromycin, have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. 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. Erythromycin 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.

    Pregnancy

    Erythromycin is classified in FDA pregnancy category B. Data available from human use during pregnancy do not support an association with erythromycin use and congenital malformations. Erythromycin crosses the placenta, but in low concentrations. One salt form, erythromycin estolate, has been observed to produce hepatotoxicity in pregnant patients. Roughly 10% of pregnant women treated with erythromycin estolate have abnormal, elevated hepatic enzymes during treatment. In most cases, the transaminases return to normal levels upon discontinuation of therapy. When pregnant women are treated with erythromycin, a formulation other than the estolate salt is recommended.

    Breast-feeding

    According to the manufacturer, erythromycin should be used with caution in breast-feeding mothers because it is excreted into breast milk. A prospective observational study assessing the safety of macrolide antibiotics during lactation found that 12.7% (n = 55) of babies exposed to macrolides via breast milk experienced adverse events including rash, diarrhea, loss of appetite, and somnolence. The adverse event rate was similar to that seen in babies in a control group whose mothers were treated with amoxicillin (8.3%). Only  2 mothers in the study received erythromycin, 10 received azithromycin, 6 received clarithromycin, and the remainder were treated with roxythromycin. A population based cohort study found that babies diagnosed with infantile hypertrophic pyloric stenosis were 2.3—3 times more likely to have been exposed to a macrolide antibiotic through breast milk during the first 90 days of life than babies not exposed during that same time period. The study did not specify which antibiotic the mothers of affected babies were prescribed; however, the majority of macrolide prescriptions were for erythromycin (72%), with 7% for azithromycin and 1.7% for clarithromycin. The American Academy of Pediatrics (AAP) considers erythromycin to be a medication that is usually compatible with breast-feeding; azithromycin and clarithromycin have not been evaluated by the AAP. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Hearing impairment

    The systemic use of erythromycin can rarely cause reversible loss of hearing or hearing impairment. Older adults, especially patients with renal or hepatic function impairment, may be at increased risk for developing hearing loss. Risk may also be increased when parenteral doses of erythromycin 4 grams/day IV or higher are given.

    Benzyl alcohol hypersensitivity, neonates

    There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. One manufacturer describes a cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of non-bilious vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. A possible dose-response effect was described with an absolute risk of IHPS of 5.1% for infants who took erythromycin for 8-14 days and 10% for infants who took erythromycin for 15-21 days. Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or neonatal Chlamydia trachomatis infections), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs. Many formulations of erythromycin lactobionate injection contain benzyl alcohol as a preservative. These preparations containing benzyl alcohol should be avoided when possible in neonates because benzyl alcohol has been associated with 'gasping syndrome', a potentially fatal condition. Benzyl alcohol may also cause allergic reactions, therefore, parenteral erythromycin formulations should not be used in patients with benzyl alcohol hypersensitivity.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Systemic erythromycin has been reported to cause QT prolongation resulting in ventricular arrhythmias of the torsade de pointes type. Fatalities have been reported. Erythromycin should be avoided in patients with known QT prolongation or in patients with ongoing proarrhythmic conditions such as uncorrected electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia), clinically significant bradycardia, and in patients receiving Class 1A or Class III antiarrhythmic agents. Elderly patients may also be more susceptible to the development of torsades de pointes than younger patients. Use erythromycin 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, myocardial infarction, hypertension, coronary artery disease, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, the elderly, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation. Ventricular tachyarrhythmias have also been reported in humans with idiopathic long QT syndrome. Patients predisposed to torsade de pointes who require IV erythromycin should not receive more than 15 mg/min. Electrolyte abnormalities should be corrected prior to therapy.

    Seizure disorder

    Erythromycin should be used cautiously in patients with a seizure disorder. There have been rare reports of seizures during erythromycin therapy.

    Myasthenia gravis

    Use with caution in patients with myasthenia gravis. Two case reports suggest that erythromycin may aggravate the weakness of patients with myasthenia gravis.

    Sexually transmitted disease

    While erythromycin may be used to treat certain sexually transmitted diseases (STD), the drug may mask or delay the symptoms of incubating gonorrhea or syphilis when given as part of an STD treatment regimen. All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.

    Geriatric

    Geriatric patients, especially those with renal or hepatic function impairment, may be at increased risk for developing hearing loss from systemic erythromycin; hearing impairment is a rare side effect. Elderly patients may be more susceptible to development of QT prolongation or torsade de pointes arrhythmias than younger patients. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    ADVERSE REACTIONS

    Severe

    erythema multiforme / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    odynophagia / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    cardiac arrest / Early / 0-1.0
    torsade de pointes / Rapid / 0-1.0
    seizures / Delayed / 0-1.0
    hearing loss / Delayed / 0-1.0
    interstitial nephritis / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    pyloric stenosis / Delayed / Incidence not known

    Moderate

    phlebitis / Rapid / 19.0-19.0
    erythema / Early / 1.0-10.0
    jaundice / Delayed / 0-10.0
    elevated hepatic enzymes / Delayed / 0-10.0
    esophagitis / Delayed / 0-1.0
    dysphagia / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    QT prolongation / Rapid / 0-1.0
    pseudomembranous colitis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known

    Mild

    skin irritation / Early / 0-25.0
    xerosis / Delayed / 1.0-10.0
    pruritus / Rapid / 1.0-10.0
    vomiting / Early / 10.0
    abdominal pain / Early / 10.0
    diarrhea / Early / 10.0
    anorexia / Delayed / 10.0
    nausea / Early / 10.0
    rash (unspecified) / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    ocular irritation / Rapid / Incidence not known

    DRUG INTERACTIONS

    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 erythromycin.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with erythromycin. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Acetaminophen; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Acetaminophen; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Acetaminophen; Tramadol: (Moderate) Administration of CYP3A4 inhibitors such as erythromycin with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Afatinib: (Major) If the concomitant use of erythromycin and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of erythromycin. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and erythromycin is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Albuterol: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Albuterol; Ipratropium: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Alfentanil: (Moderate) Erythromycin is an inhibitor of the cytochrome 3A4 isoenzyme and alfentanil is a substrate for CYP3A4. The concurrent use of erythromycin with alfentanil can significantly inhibit alfentanil clearance. As a result, the risk of prolonged or delayed respiratory depression may be increased. Monitor patients for adverse effects of alfentanil, such as hypotension, nausea, and itching. Smaller alfentanil doses may be needed if prolonged alfentanil administration is used
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and erythromycin should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval. Erythromycin administration is associated with QT prolongation and TdP. In addition, coadministration of erythromycin, a CYP3A4 inhibitor, with alfuzosin, a CYP3A4 substrate, may result in elevated alfuzosin plasma concentrations.
    Aliskiren; Amlodipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Almotriptan: (Major) Erythromycin may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and erythromycin is a CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
    Alosetron: (Moderate) Pharmacodynamic interactions between alosetron and drugs that enhance peristalsis are theoretically possible, based on opposing pharmacologic outcomes. It may be prudent to avoid use of erythromycin (when used to enhance GI motility) during alosetron treatment. Although a potential interaction has not been studied, erythromycin might negate the effect of alosetron. Caution and close monitoring are advised if these drugs are used together.
    Alprazolam: (Moderate) Drugs that may inhibit CYP3A4, such as erythromycin, may inhibit the metabolism of alprazolam. Use alprazolam and erythromycin with caution and consider alprazolam dose reduction.
    Amiodarone: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). 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. In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with Class III antiarrhythmics. Concurrent use of erythromycin with amiodarone should be avoided. In addition, erythromycin may theoretically increase plasma concentrations of amiodarone via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Amlodipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Atorvastatin: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with erythromycin, a CYP3A4 inhibitor. In healthy individuals, the plasma concentration of atorvastatin was increased 40% with coadministration of atorvastatin and erythromycin. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and erythromycin therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Benazepril: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Olmesartan: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Telmisartan: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amlodipine; Valsartan: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Amoxapine: (Moderate) Erythromycin may be used to stimulate GI motility, such as in patients with diabetic gastroparesis. Some cyclic antidepressants with substantial antimuscarinic properties, such as amoxapine, may counteract erythromycin's effectiveness in enhancing GI motility.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Both clarithromycin and erythromycin are macrolide antibiotics and coadministration would represent duplicate therapy. Additionally, coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation and TdP.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Both clarithromycin and erythromycin are macrolide antibiotics and coadministration would represent duplicate therapy. Additionally, coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation and TdP.
    Amprenavir: (Minor) Because erythromycin and amprenavir are both inhibitors and substrates of CYP3A4, increases in both amprenavir and erythromycin plasma concentrations may be noted, although the necessity of dosage adjustments has not been determined.
    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 erythromycin.
    Anthracyclines: (Major) Erythromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp); doxorubicin is a major substrate of both CYP3A4 and P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Additionally, acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Erythromycin has a possible risk of causing QT prolongation and torsades de pointes (TdP). Avoid coadministration of erythromycin and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Anticholinergics: (Moderate) Anticholinergics can antagonize the stimulatory effects of erythromycin on the GI tract (when erythromycin is used therapeutically for improving GI motility). Avoid chronic administration of antimuscarinics along with prokinetic agents under most circumstances. In addition, erythromycin is a CYP3A4 inhibitor and can reduce the metabolism of drugs metabolized by CYP3A4, including some anticholinergics.
    Apixaban: (Moderate) Use apixaban and erythromycin together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Erythromycin is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with apomorphine. Erythromycin is associated with QT prolongation and TdP. Limited data indicate that QT prolongation is also possible with apomorphine; 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 erythromycin with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased erythromycin exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in erythromycin- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Erythromycin is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Erythromycin 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 and may increase plasma concentrations of erythromycin. 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.
    Arformoterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Aripiprazole: (Major) Because both erythromycin 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, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as erythromycin. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, 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. Adults 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. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as erythromycin 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 erythromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, erythromycin should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported. Erythromycin is also associated with QT prolongation and TdP.
    Artemether; Lumefantrine: (Major) Erythromycin is a substrate/inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as erythromycin, should be avoided. Consider ECG monitoring if erythromycin must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided in combination with other agents also known to have this effect (e.g., erythromycin). Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP).
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Aspirin, ASA; Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Aspirin, ASA; Pravastatin: (Moderate) Monitor for evidence of myopathy during coadministration of pravastatin and erythromycin. With concurrent therapy of erythromycin, the risk of myopathy increases. The pravastatin labeling recommends caution during concurrent use.
    Atazanavir: (Major) The manufacturer of atazanavir states that clinically significant interactions are not expected when it is coadministered with erythromycin. However, increased plasma concentrations of erythromycin might be expected based on the inhibition of CYP3A4 by atazanavir. Additionally, because there is a potential for QT prolongation, caution is advised.
    Atazanavir; Cobicistat: (Major) Avoid concurrent use of erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor/substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and daruanavir are CYP3A4 substrates. (Major) The manufacturer of atazanavir states that clinically significant interactions are not expected when it is coadministered with erythromycin. However, increased plasma concentrations of erythromycin might be expected based on the inhibition of CYP3A4 by atazanavir. Additionally, because there is a potential for QT prolongation, caution is advised.
    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 erythromycin.
    Atorvastatin: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with erythromycin, a CYP3A4 inhibitor. In healthy individuals, the plasma concentration of atorvastatin was increased 40% with coadministration of atorvastatin and erythromycin. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and erythromycin therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Atorvastatin; Ezetimibe: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with erythromycin, a CYP3A4 inhibitor. In healthy individuals, the plasma concentration of atorvastatin was increased 40% with coadministration of atorvastatin and erythromycin. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and erythromycin therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Atropine; Difenoxin: (Minor) Diphenoxylate/difenoxin decreases GI motility. It may antagonize the muscarinic and/or prokinetic effects of erythromycin (when used for GI motility). Use these drugs in combination should be avoided.
    Atropine; Diphenoxylate: (Minor) Diphenoxylate/difenoxin decreases GI motility. It may antagonize the muscarinic and/or prokinetic effects of erythromycin (when used for GI motility). Use these drugs in combination should be avoided.
    Avanafil: (Major) Do not exceed an avanfil dose of 50 mg once every 24 hours during coadministration with erythromycin as avanafil serum conentrations may be increased. Avanafil is a substrate of and primarily metabolized by CYP3A4; erythromycin is a moderate inhibitor of CYP3A4. Erythromycin increased avanafil Cmax and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in a clinical study.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with erythromycin is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azelastine: (Minor) Coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in a slightly lower Cmax and a slightly higher AUC for azelastine compared to azelastine alone. The clinical relevance is unknown.
    Azelastine; Fluticasone: (Minor) Coadministration of orally administered azelastine (4 mg twice daily) with erythromycin (500 mg three times daily for 7 days) resulted in a slightly lower Cmax and a slightly higher AUC for azelastine compared to azelastine alone. The clinical relevance is unknown.
    Azithromycin: (Major) Avoid use of azithromycin and erythromycin together as this would be considered duplicate therapy. Cross-resistance with gram-positive organisms would be expected. Additionally, the risk for QT prolongation and torsade de pointes (TdP) increases if these drugs are administered together. Erythromycin has been associated with QT prolongation and TdP, and cases of QT prolongation and TdP have been reported during post-marketing use of azithromycin.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as erythromycin, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, erythromycin 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. An interaction with topically applied erythromycin is not expected.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) The concurrent use of erythromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Erythromycin inhibits the hepatic clearance of ergotamine via inhibition of the CYP3A4 isoenzyme. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with strong CYP3A4 inhibitors.
    Bepridil: (Severe) According to the manufacturer, bepridil is contraindicated for use with drugs that prolong the QT interval due to the risk of torsades de pointes, including erythromycin.
    Bexarotene: (Moderate) Bexarotene is metabolized by cytochrome P450 3A4. Inhibitors of CYP3A4 such as erythromycin, would be expected to increase bexarotene plasma concentrations following oral administration.
    Bicalutamide: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as erythromycin, 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
    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 erythromycin.
    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 erythromycin.
    Boceprevir: (Major) Close clinical monitoring is advised when administering erythromycin with boceprevir due to an increased potential for serious erythromycin-related adverse events, such as QT prolongation and torsade de pointes. If erythromycin 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 pathways of erythromycin and boceprevir. Both erythromycin and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (P-gp). When used in combination, the plasma concentrations of both medications may be elevated.
    Bortezomib: (Minor) Erythromycin can inhibit the hepatic metabolism of other drugs, such as borezomib, increasing their serum concentrations and potentially causing toxicity. If therapy with erythromycin is necessary, a reduction in the dose of bortezomib may be required. Such patients should be monitored carefully and lower doses should be used.
    Bosentan: (Moderate) Co-administration of bosentan with erythromycin, a CYP3A4 inhibitor, may increase the plasma concentrations of bosentan. The potential for increased bosentan effects should be monitored. The severity of this interaction is increased when erythromycin is combined with a potent CYP 2C9 inhibitor, like sulfisoxazole.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and erythromycin as 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 erythromycin is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Erythromycin is a moderate inhibitor of CYP3A4. If erythromycin is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
    Brigatinib: (Moderate) Monitor for decreased efficacy of erythromycin if coadministration is necessary. Erythromycin is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of erythromycin may decrease.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of erythromycin. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; erythromycin is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Budesonide: (Moderate) Avoid coadministration of oral budesonide and erythromycin 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; erythromycin is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and erythromycin 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; erythromycin is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Bupivacaine; Lidocaine: (Moderate) Erythromycin is a substrate and inhibitor of the cytochrome P450 (CYP) isoenzyme 3A4, and lidocaine is a CYP3A4 substrate. As compared with placebo, receipt of erythromycin 500 mg three times daily for 4 days before intravenous administration of lidocaine 1.5 mg/kg over 60 minutes did not affect the systemic lidocaine concentration. However, the plasma concentration of monoethylglycinexylidide, an active lidocaine metabolite, increased from 56 ng/ml to 80 ng/ml. The clinical significance of this interaction is not known, but the magnitude of effect on lidocaine serum concentrations may be greater when a CYP3A4 inhibitor is coadministered with a CYP1A2 inhibitor. For example, in one study, coadministration of lidocaine with both fluvoxamine (CYP1A2 inhibitor) and erythromycin has been reported to further reduce lidocaine clearance than observed with fluvoxamine alone. Fluvoxamine, a potent CYP1A2 inhibitor, has been shown to reduce lidocaine clearance by approximately 40 to 60% during in vivo studies. However, cytochrome activity was not measured during these trials. Since fluvoxamine has also been reported to moderately inhibit CYP3A4 isoenzymes, CYP3A4 inhibition may have also contributed to the reduction in lidocaine clearance. Until further data are available, it is prudent to monitor for potential lidocaine adverse effects during coadministration of systemic lidocaine and erythromycin and/or fluvoxamine.
    Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of erythromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Erythromycin 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 CYP3A4 inhibitor such as erythromycin 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 erythromycin and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Erythromycin 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 CYP3A4 inhibitor such as erythromycin 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 erythromycin with buspirone may result in significant increases in buspirone AUC; the mechanism is probably reduced buspirone metabolism via CYP3A4. If the two drugs are to be used in combination, a low dose of buspirone is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.
    Cabazitaxel: (Minor) Cabazitaxel is a CYP3A4 and P-glycoprotein (P-gp) substrate; erythromycin is a moderate inhibitor of CYP3A4 as well as a P-gp inhibitor. A drug interaction study with repeated administration of aprepitant, another moderate CYP3A4 inhibitor, did not modify the exposure to cabazitaxel; however, formal drug interaction studies have not been conducted with P-gp inhibitors. Use caution when cabazitaxel is administered concomitantly with P-gp inhibitors.
    Cabozantinib: (Moderate) Monitor for an increase in cabozantinib- and erythromycin-related adverse events if concomitant use of cabozantinib and erythromycin is necessary. Cabozantinib is primarily metabolized by CYP3A4 and erythromycin is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and erythromycin is a substrate of P-gp; plasma concentrations of erythromycin may be increased. However, the clinical relevance of this finding is unknown.
    Caffeine: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Caffeine; Ergotamine: (Severe) The concurrent use of erythromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Erythromycin inhibits the hepatic clearance of ergotamine via inhibition of the CYP3A4 isoenzyme. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with strong CYP3A4 inhibitors. (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
    Calcium-channel blockers: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Canagliflozin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Erythromycin is a PGP inhibitor/substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate/weak inhibitor of drug transporter P glycoprotein (P-gp). Erythromycin is a PGP inhibitor/substrate. Theoretically, concentrations of either drug may be increased. Patients should be monitored for changes in glycemic control and possible adverse reactions.
    Carbamazepine: (Moderate) Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Erythromycin inhibits CYP3A4 and may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations.
    Carbidopa; Levodopa; Entacapone: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as erythromycin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Erythromycin is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
    Carvedilol: (Moderate) Increased concentrations of erythromycin may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and erythromycin is a P-gp substrate.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs if coadministration of ceritinib and erythromycin is necessary; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Erythromycin is associated with QT prolongation and torsade de pointes (TdP).
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Inhibitors of these isoenzymes, such as erythromycin, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chloroquine: (Major) Concurrent use of chloroquine and erythromycin 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. Both chloroquine and erythromycin have been associated with an increased risk of QT prolongation and TdP.
    Chlorpheniramine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpromazine: (Major) Concurrent use of chlorpromazine and erythromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Erythromycin is associated with QT prolongation and TdP. Phenothiazines have also been associated with a risk of QT prolongation and/or TdP. This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
    Cilostazol: (Major) Erythromycin can inhibit the hepatic metabolism of cilostazol, increasing it's serum concentrations and potentially causing toxicity. When erythromycin or other significant CYP3A4 inhibitors are coadministered with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    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 erythromycin. 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 erythromycin with ciprofloxacin. Erythromycin is associated with QT prolongation and TdP. Ciprofloxacin is associated with a possible risk for QT prolongation and TdP and should be used cautiously with erythromycin.
    Cisapride: (Severe) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Erythromycin administration is also associated with QT prolongation TdP. Because of the potential for TdP, use of erythromycin with cisapride is contraindicated.
    Citalopram: (Major) Concurrent use of citalopram and erythromycin 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. Citalopram causes dose-dependent QT interval prolongation. Erythromycin is also associated with prolongation of the QT interval and TdP.
    Clarithromycin: (Major) Both clarithromycin and erythromycin are macrolide antibiotics and coadministration would represent duplicate therapy. Additionally, coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation and TdP.
    Clevidipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Clindamycin: (Major) Concomitant use of clindamycin and erythromycin is not recommended. Clindamycin competes with erythromycin for binding with the 50 S ribosomal subunits and can antagonize the effects of erythromycin. Additionally, concurrent use may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; erythromycin is a moderate inhibitor of CYP3A4.
    Clonazepam: (Moderate) Erythromycin may inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as clonazepam. Monitor patient clinically for enhanced clonazepam response.
    Clorazepate: (Moderate) CYP3A4 inhibitors, such as erythromycin, may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Major) Concurrent use of erythromycin and clozapine should be avoided if possible. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death and erythromycin has an established risk of QT prolongation and TdP. A case report has documented increased serum clozapine concentrations and the occurrence of a seizure when erythromycin was added to a stable dose of clozapine. Erythromycin 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 an inhibitor of CYP3A4 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 erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor/substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and daruanavir are CYP3A4 substrates.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor/substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and daruanavir are CYP3A4 substrates.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor/substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and daruanavir are CYP3A4 substrates. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic erythromycin therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of erythromycin is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of erythromycin, resume cobimetinib at the previous dose. Use an alternative to erythromycin in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; erythromycin is a moderate inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a 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) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Guaifenesin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as erythromycin, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inducers of CYP2D6, inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity; conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Perform dose adjustments as necessary to achieve stable patient response.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and erythromycin 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. Erythromycin 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 erythromycin 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 twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Major) Avoid concomitant use of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and CYP3A4 substrate, and erythromycin, a CYP3A4/P-gp substrate and CYP3A4 inhibitor. Coadministration may result in elevated concentrations of both conivaptan and erythromycin. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates, such as erythromycin, should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as erythromycin 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 erythromycin ( > 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 erythromycin 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 erythromycin ( > 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 erythromycin 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 erythromycin ( > 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.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of erythromycin with crizotinib is necessary; an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) may also occur. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Erythromycin is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP). Crizotinib is a CYP3A substrate that has also been associated with concentration-dependent QT prolongation.
    Cyclobenzaprine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with cyclobenzaprine. Erythromycin is associated with prolongation of the QT interval and TdP. Cyclobenzaprine is also associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose.
    Cyclosporine: (Major) Erythromycin may inhibit the metabolism of cyclosporine via inhibition of the CYP3A4 isoenzyme, thus increasing cyclosporine's effects and the potential for toxicity. Additionally, erythromycin has been associated with inhibition of P-glycoprotein, which leads to decreased intestinal metabolism and increased oral absorption of cyclosporine. It has been recommend to avoid cyclosporine in combination with macrolide agents or reduce the cyclosporine dosage by 50% when it is necessary to give any macrolide 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.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with erythromycin, a P-gp inhibitor. 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 erythromycin 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 erythromycin, 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.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with erythromycin, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of erythromycin, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Dapagliflozin; Saxagliptin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as erythromycin, but saxagliptin dose adjustment is not advised.
    Darunavir: (Moderate) Concentrations of erythromycin and darunavir may be increased with coadministration, as both agents are CYP3A4 substrates and inhibitors. Additionally, darunavir is administered ('boosted') with ritonavir or cobistat, which are potent CYP3A4 inhibitiors. Patients should be monitored for increased side effects.
    Darunavir; Cobicistat: (Major) Avoid concurrent use of erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor/substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor/substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and daruanavir are CYP3A4 substrates. (Moderate) Concentrations of erythromycin and darunavir may be increased with coadministration, as both agents are CYP3A4 substrates and inhibitors. Additionally, darunavir is administered ('boosted') with ritonavir or cobistat, which are potent CYP3A4 inhibitiors. Patients should be monitored for increased side effects.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Major) Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If possible, consider use of azithromycin in place of erythromycin. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together. (Major) Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. If possible, consider use of azithromycin in place of erythromycin. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together.
    Dasatinib: (Major) In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Cautious dasatinib administration is recommended to patients who have or may develop QT prolongation such as patients taking drugs that lead to QT prolongation. Erythromycin is established to have a causal association with QT prolongation and torsade de pointes (TdP). Also, erythromycin is a strong inhibitor of CYP3A4, and dasatinib is metabolized by CYP3A4; concurrent administration of erythromycin may increase concentrations of dasatinib. It is recommended that an alternative concomitant medication with no or minimal enzyme inhibition potential be selected. If dasatinib must be administered with a strong CYP3A4 inhibitor, a dasatinib dose reduction to 20 mg PO daily should be considered. Also, carefully monitor the patient for dasatinib-related toxicity. Increased erythromycin concentrations may also occur. Dasatinib is a time-dependent, weak inhibitor of CYP3A4, and erythromycin is a CYP3A4 substrate.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with erythromycin. 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; erythromycin is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with erythromycin include degarelix.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with erythromycin, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Erythromycin is associated with QT prolongation and torsade de pointes (TdP).
    Dexamethasone: (Moderate) Erythromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids such as dexamethasone. Also, dexamethasone is a moderate inducer of CYP3A4, and may increase the clearance of erythromycin, resulting in decreased plasma concentration.
    Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin.
    Dextromethorphan; Quinidine: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with quinidine. Concurrent use of erythromycin with procainamide should be avoided. In addition, erythromycin may theoretically increase plasma concentrations of quinidine via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Diazepam: (Moderate) Erythromycin may inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. Monitor patient clinically for enhanced response from diazepam.
    Dienogest; Estradiol valerate: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Digoxin: (Major) The addition of erythromycin to digoxin therapy may lead to a significant increase (43-116%) in serum digoxin concentration. 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 erythromycin. A more important factor is erythromycin 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 erythromycin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
    Dihydroergotamine: (Severe) Coadministration is contraindicated as ergot toxicity can occur, resulting in ischemic reactions and peripheral vasospasm. Erythromycin inhibits the hepatic clearance of dihydroergotamine via inhibition of the CYP3A4 isoenzyme.
    Diltiazem: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Disopyramide: (Major) Cases of life-threatening interactions have been reported for disopyramide when given with erythromycin. In vitro studies have shown that erythromycin inhibits the metabolism of disopyramide. Avoid the coadministration of disopyramide with agents that are associated with QT interval prolongation, including erythromycin. Additionally, erythromycin may inhibit the CYP3A4 metabolism of disopyramide (CYP3A4 substrate). Disopyramide and erythromycin interact both pharmacokinetically and pharmacodynamically. In two patients, erythromycin caused disopyramide serum concentrations to rise significantly, which was associated with development of QT prolongation and tachyarrhythmias. Also, the antimuscarinic actions of disopyramide can interfere with the motility-enhancing properties of erythromycin in patients receiving erythromycin for this purpose.
    Docetaxel: (Minor) Docetaxel is metabolized by cytochrome P450 3A (CYP3A4 and CYP3A5) enzymes. Erythromycin is a CYP3A4 inhibitor. In vitro studies have shown drugs that inhibit, induce, or are also metabolized by CYP3A enzymes can significantly affect the metabolism of docetaxel. In a small pharmacokinetic study, 7 patients received 2 courses of docetaxel, one with concurrent ketoconazole (docetaxel 10 mg/m2) and one without ketoconazole (docetaxel 100mg/m2). The ketoconazole dosage was 200 mg once daily for 3 days. Concurrent administration of ketoconazole decreased the clearance of docetaxel by 49% as compared to giving docetaxel alone. However, there was large interpatient variability in the reduction in clearance. Use docetaxel cautiously when administered concurrently with inducers or inhibitors of CYP3A enzymes.
    Dofetilide: (Severe) The concomitant use of erythromycin and dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Erythromycin administration is associated with QT prolongation and TdP. In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with Class III antiarrhythmics. In addition, erythromycin may theoretically increase plasma concentrations of dofetilide via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and erythromycin should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Erythromycin is associated with QT prolongation and TdP. Concurrent use may increase the risk of QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin 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 erythromycin.
    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. Erythromycin has a possible risk for QT prolongation and TdP and use of erythromycin 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 erythromycin, 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. Erythromycin has a possible risk for QT prolongation and TdP and use of erythromycin 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 erythromycin, 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.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like erythromycin, 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.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with erythromycin 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; erythromycin is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Severe) Concomitant use of dronedarone and erythromycin is contraindicated. Erythromycin administration is associated with 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.
    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 erythromycin.
    Drospirenone; Estradiol: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Dutasteride: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme and CYP3A5 isoenzymes. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors, such as erythromycin.
    Dutasteride; Tamsulosin: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme and CYP3A5 isoenzymes. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors, such as erythromycin. (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as erythromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with erythromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of erythromycin; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Major) Coadministration of efavirenz and erythromycin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Erythromycin is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of erythromycin. Efavirenz is a CYP3A4 substrate and inducer, while erythromycin is a CYP3A4 substrate and inhibitor.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and erythromycin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Erythromycin is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of erythromycin. Efavirenz is a CYP3A4 substrate and inducer, while erythromycin is a CYP3A4 substrate and inhibitor. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with erythromycin may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Erythromycin is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Severe) Erythromycin is a potent CYP3A4 inhibitor and may reduce the hepatic metabolism of CYP3A4 substrates. Eletriptan is metabolized via CYP3A4. Medications that significantly inhibit the CYP3A4 isozyme, such as erythromycin, can cause increased eletriptan concentrations. Concomitant use of erythromycin and eletriptan resulted in a 2-fold increase in the Cmax and about a 4-fold increase in the AUC of eletriptan. Do not use eletriptan within at least 72 hours of using erythromycin or any other potent CYP3A4 inhibitor.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of erythromycin (including erythromycin; sulfisoxazole) and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of erythromycin and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both erythromycin and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and erythromycin can independently prolong the QT interval, and coadministration increases this risk. Erythromycin is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as erythromycin, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin 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 erythromycin.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin 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 erythromycin. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enalapril; Felodipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Entacapone: (Moderate) Entacapone should be given cautiously with drugs known to interfere with biliary excretion, glucuronidation or intestinal beta-glucuronidation such as erythromycin. Decreased biliary excretion of entacapone may occur if these agents are given concurrently.
    Eplerenone: (Major) Eplerenone is metabolized by the CYP3A4 pathway. Coadministration of eplerenone with erythromycin has resulted in 2- to 2.9-fold increases in eplerenone AUC. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently for the treatment of hypertension, initiate eplerenone at 25 mg PO once daily. The dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response.
    Ergonovine: (Severe) The concurrent use of certain macrolides, such as erythromycin, with ergot alkaloids is considered contraindicated.
    Ergotamine: (Severe) The concurrent use of erythromycin and ergotamine is contraindicated due to the risk for ergot toxicity; severe vasospastic adverse events, including extremity ischemia that may require amputation, can occur. Erythromycin inhibits the hepatic clearance of ergotamine via inhibition of the CYP3A4 isoenzyme. Rare cases of cerebral ischemia, which may result in death, have also been reported when ergotamine was administered with strong CYP3A4 inhibitors.
    Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval, such as erythromycin, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with erythromycin is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both erythromycin and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Erythromycin is a moderate CYP3A4 inhibitor. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with erythromycin may also increase erlotinib exposure.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as erythromycin, should be done with caution and close monitoring. In addition, escitalopram is metabolized by CYP3A4. Theoretically, erythromycin may inhibit this enzyme and lead to elevated plasma levels of this SSRI. However, because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
    Estazolam: (Moderate) Erythromycin is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as erythromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as erythromycin may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Levonorgestrel: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norethindrone: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norgestimate: (Minor) As erythromycin inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4, such as erythromycin, 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.
    Eszopiclone: (Moderate) Clinically relevant interaction, possibly requiring a reduction of eszopiclone dose, may occur when eszopiclone is administered with erythromycin (a moderate CYP3A4 inhibitor). When eszopiclone is administered with a potent CYP3A4 inhibitor, such as clarithromycin, the adult dose should not exceed 2 mg/day. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure may result in next-day psychomotor or memory impairment.
    Ethinyl Estradiol; Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as erythromycin may increase the serum concentration of etonogestrel.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as erythromycin may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with erythromycin. Erythromycin is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor and erythromycin is a CYP3A4 and PGP substrate/inhibitor. Caution is warranted if these drugs are coadministered.
    Everolimus: (Major) A dose adjustment of everolimus is necessary when prescribed with erythromycin due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. For patients with subependymal giant cell astrocytoma (SEGA) with TSC, the recommended starting dose of Afinitor/Afinitor Disperz is 2.5 mg/m2 once daily, rounded to the nearest tablet strength; subsequent dosing should be guided by therapeutic drug monitoring (TDM), with administration every other day if dose reduction is required for patients receiving the lowest available tablet strength. If erythromycin is discontinued, increase everolimus to its original dose after a washout period of 2 to 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); erythromycin is a moderate CYP3A4 and P-gp inhibitor. Coadministration with erythromycin increased everolimus exposure by 4.4-fold.
    Ezetimibe; Simvastatin: (Severe) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Ezogabine: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with erythromycin include ezogabine.
    Felodipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Fentanyl: (Moderate) Fentanyl is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as erythromycin, may increase the bioavailability of swallowed fentanyl and/or decrease systemic clearance of fentanyl leading to increased or prolonged effects.
    Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod include erythromycin.
    Flecainide: (Major) Concurrent use of flecainide and erythromycin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Erythromycin administration is associated with QT prolongation and TdP. In addition, erythromycin may theoretically increase plasma concentrations of flecainide via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Flibanserin: (Severe) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as erythromycin, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Severe) Fluconazole has been associated with QT prolongation and erythromycin has been specifically established to have a causal association with QT prolongation and torsade de pointes (TdP); therefore, concomitant use is contraindicated. Additionally, fluconazole is an inhibitor of CYP3A4 and erythromycin is a known inhibitor and substrate of CYP3A4 and P-glycoprotein. Consider use of azithromycin in place of erythromycin. A retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A. Because fluconazole inhibits CYP3A4 and becomes a more potent inhibitor at higher dosages (>=200 to 400 mg/day), the co-use of fluconazole and erythromycin should be approached with caution.
    Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include erythromycin.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include erythromycin. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with olanzapine. Erythromycin is associated with prolongation of the QT interval and TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Fluphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with fluphenazine. Erythromycin is associated with prolongation of the QT interval and TdP. Fluphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Flurazepam: (Moderate) Erythromycin may inhibit the CYP3A4-mediated metabolism of flurazepam, Monitor patient clinically for enhanced benzodiazepine response.
    Fluticasone; Salmeterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists, like salmeterol. Additionally, salmeterol is a CYP3A4 substrates, and erythromycin, a CYP3A4 inhbitor, may increase salmeterol concentrations. A small study of 13 healthy subjects resulted in a 40% increase in salmeterol maximum concentrations (Cmax) during concurrent repeat-dose administration of erythromycin. The QT interval increased by 5.8 msec and a small, but statistically significant increase in heart rate occurred (3.6 beats/minute). No dose adjustment is suggested, but caution is advised. The effects of salmeterol on the cardiovascular system, as well as side effects like headache, tremor, and nervousness, may be potentiated.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Fluvastatin: (Major) The risk of developing myopathy and/or rhabdomyolysis with HMG-CoA reductase inhibitors, such as fluvastatin, is increased if coadministered with erythromycin. Fluvastatin is partially metabolized by CYP3A4, and erythromycin is a potent CYP3A4 inhibitor. However, according to the manufacturer, coadministration of erythromycin did not significantly alter the pharmacokinetic disposition of fluvastatin.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and erythromycin. Erythromycin is associated with QT prolongation and TdP; fatalities have been reported. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with erythromycin. Erythromycin is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with erythromycin, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Formoterol; Mometasone: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Fosamprenavir: (Moderate) Because erythromycin and fosamprenavir are both inhibitors and substrates of CYP3A4, increases in both amprenavir and erythromycin plasma concentrations may be noted, although the necessity of dosage adjustments has not been determined.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as erythromycin. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Erythromycin is also associated with QT prolongation and TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosfomycin: (Moderate) Erythromycin, when used to increase gastrointestinal motility, may decrease the systemic absorption of fosfomycin when the drugs are coadministered.
    Galantamine: (Minor) Galantamine is a primary substrate of CYP3A4 and coadministration with CYP3A4 inhibitors may increase the systemic exposure of galantamine. In one pharmacokinetic study, coadministration of galantamine with the moderate CYP3A4 inhibitor erythromycin at a dose of 500 mg four times a day for 4 days resulted in a minimal increase in the AUC of galantamine (10% increase). The clinical significance of this interaction, if any, is unknown.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and erythromycin are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and erythromycin is a moderate CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inhibitors, administration of a single 250 mg gefitinib dose with a strong CYP3A4 inhibitor increased the mean AUC of gefitinib by 80%.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with gemifloxacin. Erythromycin is associated with QT prolongation and TdP, and gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and erythromycin together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Cases ofTdP have been spontaneously reported during postmarketing surveillance in patients receiving erythromycin. Fatalities have been reported.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and erythromycin as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and erythromycin are both substrates and inhibitors of P-glycoprotein (P-gp). Additionally, glecaprevir is a substrate of organic anion transporting polypeptide (OATP) 1B1/3 and erythromycin is an inhibitor of OATP1B1/3. (Moderate) Caution is advised with the coadministration of pibrentasvir and erythromycin as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and erythromycin are substrates and inhibitors of P-glycoprotein (P-gp).
    Glycopyrrolate; Formoterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Goserelin: (Major) Erythromycin should be used cautiously and with close monitoring with goserelin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), granisetron and erythromycin should be used together cautiously. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron with drugs known to prolong the QT interval or are arrhythmogenic, may result in clinical consequences. Erythromycin administration is associated with QT prolongation and TdP.
    Grapefruit juice: (Moderate) Erythromycin is metabolized via the cytochrome CYP 3A4 isozyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. In a study of healthy volunteers, grapefruit juice significantly increased the bioavailability of erythromycin. Patients should probably not significantly alter their usual intake of grapefruit juice during therapy, since many of the common, yet troublesome, side effects of erythromycin appear to be dose-related.
    Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Inhibitors of the hepatic CYP450 isoenzyme CYP1A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine related side effects, the dosage of caffeine containing products may need to be reduced.
    Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guanfacine: (Major) Erythromycin may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon erythromycin discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and erythromycin is a moderate CYP3A4 inhibitor.
    Guarana: (Moderate) Inhibitors of the hepatic CYP450 isoenzyme CYP1A2 may inhibit the hepatic oxidative metabolism of caffeine, which is an active component of guarana. Such medications include erythromycin. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. Such patients should reduce their intake of guarana.
    Halofantrine: (Severe) Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes. Halofantrine should be avoided in patients receiving drugs which may induce QT prolongation, such as erythromycin.
    Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with erythromycin. Halogenated anesthetics can prolong the QT interval and erythromycin administration is associated with QT prolongation and torsades de pointes (TdP).
    Haloperidol: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with haloperidol. It is prudent to use caution and carefully weighing the risks and benefits of these agents versus alternative treatment options. Erythromycin has an established risk for QT prolongation and TdP. QT prolongation and TdP have also been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) of haloperidol may be associated with a higher risk of QT prolongation. In addition, inhibition of CYP3A4 by eythromycin may result in elevated haloperidol concentrations, thereby increasing the risk of adverse effects, including QT prolongation.
    Homatropine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Losartan is metabolized to an active metabolite E-3174. The AUC of this active metabolite of oral losartan is not affected by erythromycin, a CYP3A4 inhibitor; however, the AUC of losartan is increased by 30%.
    Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Ibuprofen: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and erythromycin are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocortisone: (Moderate) Erythromycin inhibits CYP3A4 and has the potential to result in increased plasma concentrations of corticosteroids. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and erythromycin. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. Erythromycin is associated with QT prolongation and TdP.
    Hydroxyprogesterone: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole. It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes, like erythromycin, would have a similar effect.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include erythromycin.
    Ibrutinib: (Major) If coadministered with erythromycin, initiate ibrutinib therapy at a reduced dose of 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of erythromycin, the Cmax and AUC values of ibrutinib increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Ibutilide: (Major) Concurrent use of erythromycin with Class III antiarrhythmic agents should be avoided. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with Class III antiarrhythmics. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with erythromycin, a CYP3A substrate, as erythromycin toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as erythromycin.
    Imatinib: (Moderate) Any agent that inhibits cytochrome P450 3A4, such as erythromycin, may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions.
    Indacaterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). Erythromycin, a dual CYP3A4 and P-gp inhibitor, may increase indacaterol drug concentrations. Coadministration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mcg qid x 7 days) resulted in a 1.4-fold increase in indacaterol AUC, and 1.2-fold increase in indacaterol Cmax. No dose adjustment is suggested, but caution is advised. The effects of indacaterol on the cardiovascular system, and side effects like headache, tremor, or nervousness may be potentiated.
    Indacaterol; Glycopyrrolate: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). Erythromycin, a dual CYP3A4 and P-gp inhibitor, may increase indacaterol drug concentrations. Coadministration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mcg qid x 7 days) resulted in a 1.4-fold increase in indacaterol AUC, and 1.2-fold increase in indacaterol Cmax. No dose adjustment is suggested, but caution is advised. The effects of indacaterol on the cardiovascular system, and side effects like headache, tremor, or nervousness may be potentiated.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with erythromycin due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Erythromycin is associated with QT prolongation and TdP.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with erythromycin, a CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Erythromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp); irinotecan is a CYP3A4 and P-gp substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with erythromycin may result in increased serum concentrations of both drugs. Erythromycin is a substrate and inhibitor of the hepatic isoenzyme CYP3A4 and substrate of the drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Erythromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. Coadministration of oral erythromycin 500 mg and rifampin 600 mg to healthy patients led to a reduced erythromycin maximum serum concentration (Cmax) and an increased clearance. Specifically, as monotherapy, the median erythromycin Cmax was 1.34 mg/L (range, 0.4 to 3.16), and the median apparent oral clearance was 96 L/hour (range, 37 to 250). In combination with rifampin, the median erythromycin Cmax was 0.72 mg/L (range, 0.06 to 1.66), and the median apparent oral clearance was 197 L/hour (range, 102 to 2015).
    Isoniazid, INH; Rifampin: (Major) Erythromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. Coadministration of oral erythromycin 500 mg and rifampin 600 mg to healthy patients led to a reduced erythromycin maximum serum concentration (Cmax) and an increased clearance. Specifically, as monotherapy, the median erythromycin Cmax was 1.34 mg/L (range, 0.4 to 3.16), and the median apparent oral clearance was 96 L/hour (range, 37 to 250). In combination with rifampin, the median erythromycin Cmax was 0.72 mg/L (range, 0.06 to 1.66), and the median apparent oral clearance was 197 L/hour (range, 102 to 2015).
    Isradipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as erythromycin. Consider use of azithromycin in place of erythromycin. Both erythromycin and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Following concurrent administration of a single erythromycin 1 g dose with a single itraconazole 200 mg dose, the mean Cmax and AUC of itraconazole were increased by 44% and 35%, respectively. Further, a retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors (nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin) increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1,476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivabradine: (Major) Avoid coadministration of ivabradine and erythromycin as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; erythromycin inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If erythromcyin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate, and erythromycin is a moderate CYP3A inhibitor. Coadministration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); erythromycin is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase erythromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Moderate) Ixabepilone is a CYP3A4 substrate, and concomitant use with mild or moderate CYP3A4 inhibitors such as erythromycin has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with erythromycin; closely monitor patients for ixabepilone-related toxicities.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as erythromycin. Both erythromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both ketoconazole and erythromycin are CYP3A4 inhibitors and substrates. Use of these drugs together may result in elevated plasma concentrations of both drugs, further increasing the risk for adverse effects. A retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors (nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin) increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1,476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A.
    Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like macrolides, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Lapatinib: (Major) Lapatinib is a CYP3A4 substrate/inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate/inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Erythromycin is a P-glycoprotein (P-gp) inhibitor, a CYP3A4 substrate/inhibitor. If lapatinib will be coadministered with a CYP3A4 substrate, such as erythromycin, exercise caution and consider dose reduction of erythromycin. Concurrent administration of lapatinib with a P-gp and CYP3A4 inhibitor such as erythromycin is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and erythromycin can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of erythromycin and ledipasvir; sofosbuvir. Both ledipasvir and erythromycin are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Lenvatinib: (Major) Lenvatinib should be used cautiously and with close monitoring with erythromycin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include erythromycin.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include erythromycin.
    Levalbuterol: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Levobupivacaine: (Moderate) Levobupivacaine is metabolized by cytochrome P450 (CYP) isoenzymes 3A4 and1A2. Known inhibitors of CYP 3A4, such as erythromycin, may result in increased systemic levels of levobupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of levobupivacaine may be needed.
    Levofloxacin: (Major) Concurrent use of erythromycin and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Erythromycin therapy is also associated with QT prolongation and TdP.
    Levomethadyl: (Severe) Erythromycin is generally considered by experts to have an established risk for QT prolongation and torsades de pointes. Concurrent use of levomethadyl and erythromycin is contraindicated due to the risk additive of QT prolongation.
    Lidocaine: (Moderate) Erythromycin is a substrate and inhibitor of the cytochrome P450 (CYP) isoenzyme 3A4, and lidocaine is a CYP3A4 substrate. As compared with placebo, receipt of erythromycin 500 mg three times daily for 4 days before intravenous administration of lidocaine 1.5 mg/kg over 60 minutes did not affect the systemic lidocaine concentration. However, the plasma concentration of monoethylglycinexylidide, an active lidocaine metabolite, increased from 56 ng/ml to 80 ng/ml. The clinical significance of this interaction is not known, but the magnitude of effect on lidocaine serum concentrations may be greater when a CYP3A4 inhibitor is coadministered with a CYP1A2 inhibitor. For example, in one study, coadministration of lidocaine with both fluvoxamine (CYP1A2 inhibitor) and erythromycin has been reported to further reduce lidocaine clearance than observed with fluvoxamine alone. Fluvoxamine, a potent CYP1A2 inhibitor, has been shown to reduce lidocaine clearance by approximately 40 to 60% during in vivo studies. However, cytochrome activity was not measured during these trials. Since fluvoxamine has also been reported to moderately inhibit CYP3A4 isoenzymes, CYP3A4 inhibition may have also contributed to the reduction in lidocaine clearance. Until further data are available, it is prudent to monitor for potential lidocaine adverse effects during coadministration of systemic lidocaine and erythromycin and/or fluvoxamine.
    Lincomycin: (Major) Lincomycin and macrolide antimicrobials are bactericidal or bacteriostatic via the same or similar mechanisms of action. Antagonism in vitro has been demonstrated when lincomycin was coadministered with erythromycin. It is not recommended to administer these agents together in any combination due to potential antagonism. The manufacturer of lincomycin does not recommend concurrent use of lincomycin with macrolides.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with erythromycin. Lithium has been associated with QT prolongation. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP).
    Lomefloxacin: (Major) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as erythromycin, should be used cautiously when given concurrently with lomefloxacin.
    Lomitapide: (Severe) Concomitant use of erythromycin and lomitapide is contraindicated. If treatment with erythromycin is unavoidable, lomitapide should be stopped during the course of treatment. Erythromycin is a moderate CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use.
    Loperamide: (Major) Avoid administering loperamide with drugs that enhance peristalsis, such as erythromycin (when used to enhance GI motility). Coadministration of loperamide with erythromycin may also increase the risk for QT prolongation and torsade de pointes (TdP). Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. In addition, the plasma concentrations of loperamide (a CYP3A4 and P-glycoprotein (P-gp) substrate) may be increased when administered concurrently with erythromycin (a CYP3A4 and P-gp inhibitor), further increasing the risk of toxicity. Use of these drugs together may also increase the risk other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Avoid administering loperamide with drugs that enhance peristalsis, such as erythromycin (when used to enhance GI motility). Coadministration of loperamide with erythromycin may also increase the risk for QT prolongation and torsade de pointes (TdP). Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. In addition, the plasma concentrations of loperamide (a CYP3A4 and P-glycoprotein (P-gp) substrate) may be increased when administered concurrently with erythromycin (a CYP3A4 and P-gp inhibitor), further increasing the risk of toxicity. Use of these drugs together may also increase the risk other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with lopinavir; ritonavir. Erythromycin is associated with prolongation of the QT interval and TdP. Lopinavir; ritonavir is also associated with QT prolongation. In addition, lopinavir; ritonavir inhibits CYP3A4 and erythromycin is a CYP3A4 substrate/inhibitor. Coadministration may result in elevated erythromycin plasma concentrations and an added risk of adverse reactions such as QT prolongation.
    Loratadine: (Minor) Erythromycin has been shown to interfere with the metabolism of loratadine, probably through inhibition of CYP3A4, resulting in increased serum concentrations of loratadine and its metabolite. Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events.
    Loratadine; Pseudoephedrine: (Minor) Erythromycin has been shown to interfere with the metabolism of loratadine, probably through inhibition of CYP3A4, resulting in increased serum concentrations of loratadine and its metabolite. Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events.
    Losartan: (Minor) Losartan is metabolized to an active metabolite E-3174. The AUC of this active metabolite of oral losartan is not affected by erythromycin, a CYP3A4 inhibitor; however, the AUC of losartan is increased by 30%.
    Lovastatin: (Severe) Concurrent use of lovastatin and erythromycin is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with strong CYP3A4 inhibitors including erythromycin. If no alternative to a short course of treatment with erythromycin is available, a brief suspension of lovastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy.
    Lovastatin; Niacin: (Severe) Concurrent use of lovastatin and erythromycin is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with strong CYP3A4 inhibitors including erythromycin. If no alternative to a short course of treatment with erythromycin is available, a brief suspension of lovastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy.
    Lumacaftor; Ivacaftor: (Major) If erythromcyin and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate, and erythromycin is a moderate CYP3A inhibitor. Coadministration with fluconazole, another moderate CYP3A inhibitor, increased ivacaftor exposure by 3-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); erythromycin is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase erythromycin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of erythromycin; avoid concurrent use if possible. If concomitant use of erythromycin is necessary, monitor for microbiological activity and signs and symptoms of lumacaftor; ivacaftor toxicity. Erythromycin is a substrate and inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. The enzyme induction effects of lumacaftor may decrease the systemic exposure of erythromycin and decrease its therapeutic efficacy. In addition, the inhibitory effects of erythromycin may increase the systemic exposure of ivacaftor, although no dosage adjustment is recommended for moderate CYP3A inhibition.
    Lurasidone: (Major) Erythromycin is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
    Maprotiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with maprotiline. Erythromycin is associated with prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some cyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin's effectiveness.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with erythromycin is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A/P-glycoprotein (P-gp) substrate and erythromycin is a CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with mefloquine. Erythromycin is associated with prolongation of the QT interval and TdP. There is also evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp) and erythromycin is a CYP3A4 and P-gp inhibitor. Coadministration may decrease the clearance of mefloquine and increase mefloquine systemic exposure further increasing the risk for QT prolongation.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin.
    Mesoridazine: (Severe) Erythromycin is generally considered by experts to have an established risk for QT prolongation and torsades de pointes. Given the potential for QT prolongation, mesoridazine should not be used with drugs that cause QT prolongation including erythromycin.
    Metaproterenol: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Metformin; Repaglinide: (Moderate) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Clarithromycin inhibits this enzyme and has been found to produce a greater hypoglycemic effect from repaglinide. These are clinically significant increases in repaglinide plasma levels which may necessitate a repaglinide dose adjustment. Erythromycin is likely to interact in a similar fashion.
    Metformin; Saxagliptin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as erythromycin, but saxagliptin dose adjustment is not advised.
    Methadone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with methadone. The need to coadminister these drugs should be done with careful assessment of treatment risks versus benefits. Erythromycin is associated with prolongation of the QT interval and TdP. Methadone is also considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses averaging approximately 400 mg/day in adult patients. In addition, methadone is a substrate for CYP3A4 and P-glycoprotein (P-gp), while erythromycin is a CYP3A4 and P-gp inhibitor. Concurrent use may result in increased serum concentrations of methadone.
    Methylergonovine: (Severe) Erythromycin should not be coadministered with methylergonovine due to the risk of ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). Erythromycin inhibits the metabolism of ergot alkaloids via inhibition of the CYP3A4 enzyme.
    Methylprednisolone: (Minor) Erythromycin decreases the clearance of methylprednisolone. The clinical implications of these pharmacokinetic interactions are uncertain, but some studies have used the interaction to dose-reduce methylprednisolone in acutely asthmatic patients without compromising steroid efficacy.
    Methysergide: (Severe) The concurrent use of certain macrolides, such as erythromycin, with ergot alkaloids is considered contraindicated.
    Metronidazole: (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 erythromycin.
    Midazolam: (Major) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as erythromycin, can potentiate the clinical effects of midazolam. Use this combination with caution.
    Midostaurin: (Major) The concomitant use of midostaurin and erythromycin may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. Electrolyte abnormalities should be corrected prior to erythromycin therapy. Patients predisposed to torsade de pointes (TdP) who require IV erythromycin should not receive more than 15 mg/min. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Systemic erythromycin has been reported to cause QT prolongation resulting in ventricular arrhythmias of the TdP type; fatalities have been reported. Elderly patients may also be more susceptible to the development of torsades de pointes than younger patients.
    Mifepristone, RU-486: (Major) Mifepristone has been associated with dose-dependent prolongation of the QT interval and is a CYP3A4 substrate. Drugs that are moderate CYP3A4 inhibitors that also prolong the QT interval, such as erythromycin, should be used with caution and close monitoring. To minimize the risk of QT prolongation and torsade de pointes (TdP), the lowest effective dose of mifepristone should always be used for the treatment of chronic endocrine conditions (Cushing's syndrome). There is no experience with high exposure o fmifepristone or concomitant use with other QT prolonging drugs. Erythromycin is also associated with prolongation of the QT interval and TdP. The use of mifepristone with CYP3A inhibitors may result in increased mifepristone concentrations and an increased risk of QT prolongation.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and erythromycin. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other QT prolonging medications. Erythromycin is associated with QT prolongation and TdP; fatalities have been reported. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in concentrations of mirtazapine, a CYP3A4 substrate, are possible. Therefore, caution is advised during concurrent use of mirtazapine and macrolide antibiotics that are CYP3A4 inhibitors such as erythromycin.
    Mitotane: (Major) Use caution if mitotane and erythromycin are used concomitantly, and monitor for decreased efficacy of erythromycin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and erythromycin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of erythromycin. When oral erythromycin 500 mg was coadministered with another strong CYP3A inducer, rifampin (600 mg), to healthy patients, the median erythromycin Cmax was 0.72 mg/L (range, 0.06 to 1.66), compared to 1.34 mg/L (range, 0.4 to 3.16) with erythromycin monotherapy; the median apparent oral clearance was 197 L/hour (range, 102 to 2015 L/hour) compared to 96 L/hour (range, 37 to 250 L/hour), respectively.
    Modafinil: (Moderate) Erythromycin can inhibit the hepatic metabolism of other drugs, such as modafinil, increasing their serum concentrations and potentially causing toxicity.
    Moxifloxacin: (Major) Concurrent use of erythromycin and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Erythromycin is associated with QT prolongation and TdP. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with erythromycin. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; erythromycin is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Naloxegol: (Major) Concomitant use of naloxegol with moderate CYP3A4 inhibitors should be avoided. Naloxegol is metabolized primarily by the CYP3A enzyme system. Moderate CYP3A4 inhibitors, such as erythromycin, may increase the risk of naloxegol related adverse reactions. If concomitant use is unavoidable, decrease the dosage of naloxegol to 12.5 mg PO once daily and monitor for adverse reactions.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Erythromycin is a CYP3A4 inhibitor. In vitro, the metabolism of paclitaxel is inhibited by various agents (e.g., ketoconazole, verapamil, diazepam, quinidine, dexamethasone, tenopiside, etoposide, and vincristine) but concentrations used exceeded those found in vivo following normal therapeutic doses. Closely monitor patients for toxicity when administering paclitaxel with any of these agents.
    Neratinib: (Major) Avoid concomitant use of erythromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Nevirapine: (Moderate) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, including erythromycin, may require dosage adjustments.
    Niacin; Simvastatin: (Severe) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Nicardipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Nifedipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Erythromycin has a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and erythromycin is an inhibitor and a substrate of CYP3A4 and P-gp; nilotinib and/or erythromycin levels may increase. If the use of erythromycin is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Nimodipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Nintedanib: (Moderate) Erythromycin is a moderate inhibitor of P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of erythromycin and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nisoldipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with norfloxacin. Erythromycin is associated with QT prolongation and TdP. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with octreotide. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Erythromycin is associated with prolongation of the QT interval and TdP.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with ofloxacin. Erythromycin is associated with QT prolongation and TdP. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with olanzapine. Erythromycin is associated with prolongation of the QT interval and TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Olaparib: (Major) Avoid coadministration of olaparib with erythromycin and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and erythromycin is a moderate CYP3A4 inhibitor.
    Olodaterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). Erythromycin, a dual moderate CYP3A4 and a P-gp inhibitor, might increase olodaterol drug concentrations. Coadministration of olodaterol inhalation with a strong CYP3A4/P-gp dual inhibitor resulted in a 1.7-fold increase in olodaterol AUC. No dose adjustment is suggested, but caution is advised. The effects of olodaterol on the cardiovascular system, and side effects like headache, tremor, or nervousness may be potentiated.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Major) Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. If possible, consider use of azithromycin in place of erythromycin. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together.
    Ondansetron: (Major) If ondansetron and erythromycin must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Erythromycin is also associated with QT prolongation and TdP.
    Oral Contraceptives: (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.
    Oritavancin: (Moderate) Erythromycin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of erythromycin may be reduced if these drugs are administered concurrently.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of erythromycin with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Erythromycin is also associated with QT prolongation as well as torsade de pointes (TdP).
    Oxaliplatin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of erythromycin with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Erythromycin is associated with QT prolongation and torsade de pointes (TdP); QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
    Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as erythromycin, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. Erythromycin is a CYP3A4 inhibitor. In vitro, the metabolism of paclitaxel is inhibited by various agents (e.g., ketoconazole, verapamil, diazepam, quinidine, dexamethasone, tenopiside, etoposide, and vincristine) but concentrations used exceeded those found in vivo following normal therapeutic doses. Closely monitor patients for toxicity when administering paclitaxel with any of these agents.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as erythromycin. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Panobinostat: (Major) The co-administration of panobinostat with erythromycin or erythromycin; sulfisoxazole is not recommended; QT prolongation has been reported with panobinostat and erythromycin and the levels of panobinostat may increase. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of erythromycin and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Erythromycin is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
    Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as erythromycin. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Pasireotide: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Cautious use of pasireotide and erythromycin is needed, as coadministration may have additive effects on the prolongation of the QT interval.
    Pazopanib: (Major) Pazopanib and erythromycin have been reported to prolong the QT interval; coadministration is not advised. If pazopanib and erythromycin must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a substrate for CYP3A4 and P-glycoprotein (P-gp) and a weak inhibitor of CYP3A4. Erythromycin is an inhibitor of CYP3A4 and P-gp and a CYP3A4 substrate. Concurrent administration of erythromycin and pazopanib may result in increased pazopanib and/or erythromycin concentrations. Dose reduction of pazopanib should be considered during coadministration.
    Pentamidine: (Major) Pentamidine has been associated with serious cardiac arrhythmias including QT prolongation. The drug should be used cautiously, if at all, in patients receiving agents which may cause QT prolongation or torsade de pointes (TdP). Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP).
    Perindopril; Amlodipine: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Perphenazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with perphenazine. Erythromycin is associated with prolongation of the QT interval and TdP. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with perphenazine. Erythromycin is associated with prolongation of the QT interval and TdP. Perphenazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Phenicol Derivatives: (Major) Chloramphenicol and macrolides are bactericidal or bacteriostatic via the same or similar mechanisms of action. Antagonism in vitro has been demonstrated. It is not recommended to administer these agents together in any combination due to potential antagonism.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as erythromycin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Concurrent use of pimozide and macrolides is contraindicated. Pimozide is metabolized primarily through CYP3A4, and macrolide antibiotics are CYP3A4 inhibitors. Elevated pimozide concentrations occurring through inhibition of CYP3A4 can lead to QT prolongation, ventricular arrhythmias, and sudden death. Two sudden deaths have been reported when clarithromycin was added to pimozide therapy.
    Pirbuterol: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Posaconazole: (Severe) The concurrent use of posaconazole and erythromycin is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Consider use of azithromycin in place of erythromycin. Both erythromycin and posaconazole are potent inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of erythromycin. Further, both posaconazole and erythromycin are inhibitors and substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and erythromycin and an increased risk for serious adverse events. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as erythromycin.
    Pramlintide: (Major) Pramlintide therapy should not be considered in patients taking medications that alter gastric motility. Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Drugs that stimulate GI motility and could antagonize the effects of pramlintide include erythromycin.
    Pravastatin: (Moderate) Monitor for evidence of myopathy during coadministration of pravastatin and erythromycin. With concurrent therapy of erythromycin, the risk of myopathy increases. The pravastatin labeling recommends caution during concurrent use.
    Praziquantel: (Moderate) Erythromycin is a significant CYP3A4 inhibitor and may reduce metabolism of praziquantel. This interaction may be beneficial. The combination may prolong the exposure of the parasites to praziquantel and may not result in an increased risk of side effects.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include erythromycin.
    Procainamide: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with procainamide. Concurrent use of erythromycin with procainamide should be avoided.
    Prochlorperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Erythromycin is associated with prolongation of the QT interval and TdP. Phenothiazines, such as prochlorperazine, have also been reported to prolong the QT interval.
    Progesterone: (Minor) The metabolism of progesterone may be inhibited by erythromycin, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include erythromycin.
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with propafenone. Erythromycin is associated with prolongation of the QT interval and TdP. Propafenone, a Class IC antiarrhythmic, also increases the QT interval, but largely due to prolongation of the QRS interval. In addition, erythromycin may theoretically increase plasma concentrations of propafenone via inhibition of CYP3A4. Higher propafenone plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Quazepam: (Moderate) Erythromycin can decrease the hepatic metabolism of quazepam if administered concomitantly. Patients receiving quazepam should be monitored for signs of an exaggerated response if erythromycin is used concomitantly.
    Quetiapine: (Major) Erythromycin has an established causal association with QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase QT interval. In addition, CYP3A4 is involved in the metabolism of quetiapine. Erythromycin may increase plasma concentrations of quetiapine through CYP3A4 inhibition. Coadministration of with erythromycin resulted in decreased quetiapine clearance, increased quetiapine plasma concentrations, and prolonged quetiapine half-life. Nineteen patients received quetiapine (200 mg PO twice a day) for roughly 7 days, then erythromycin (500 mg PO 3 times a day) was added for 5 days. Mean quetiapine AUC increased 129% (range 15 to 300%) and the half-life was elevated from 7 to 16 hours. Pharmacokinetic changes of this magnitude will most likely increase the incidence of adverse events, such as drowsiness, orthostatic hypotension, xerostomia, and dizziness. The manufacturer of quetiapine recommends a reduced dose during concurrent administration of CYP3A4 inhibitors. Macrolides that do not inhibit CYP3A4, such as azithromycin and dirithromycin, should be considered in patients taking quetiapine.
    Quinidine: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with quinidine. Concurrent use of erythromycin with procainamide should be avoided. In addition, erythromycin may theoretically increase plasma concentrations of quinidine via inhibition of CYP3A4. Higher antiarrhythmic plasma concentrations increases the potential risk of QT prolongation, TdP or other proarrhythmias.
    Quinine: (Major) Concurrent use of quinine with erythromycin should be avoided due to the risk for QT prolongation and torsade de pointes (TdP). Both quinine and erythromycin have been associated with prolongation of the QT interval. In addition, because both erythromycin and quinine are substrates and inhibitors of CYP3A4; coadministration may result in elevated plasma concentration of both drugs, causing an increased risk for adverse events.
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as erythromycin, may lead to increases in the serum concentrations of ramelteon.
    Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as erythromycin. Furthermore, the dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with erythromycin, a moderate CYP3A inhibitor. Furthermore, erythromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
    Red Yeast Rice: (Severe) The concurrent use of erythromycin is not recommended during lovastatin therapy. Erythromycin potently inhibits the metabolism of certain statins via the CYP3A4 isoenzyme and increase the risk of myopathy and rhabdomyolysis. Several case reports have described the development of rhabdomyolysis after erythromycin was added to a drug regimen containing lovastatin. Symptoms improved after erythromycin was discontinued. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, brief interruption of lovastatin therapy should be considered. There are no known adverse effects with short-term discontinuation of statins. Other HMG-CoA reductase inhibitors which are significant CYP3A4 substrates include atorvastatin and cerivastatin. Coadministration of atorvastatin with erythromycin increases atorvastatin plasma concentrations by about 40%. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as erythromycin. Coadministration of a single dose of rosuvastatin (80 mg) with erythromycin results in a 20% decrease in the AUC of rosuvastatin. Erythromycin (500 mg, single dose) does not affect steady state plasma levels of fluvastatin when administered 40 mg once daily. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with erythromycin. In general, erythromycin should be used with caution in patients receiving HMG CoA-reductase inhibitors; patients should be monitored closely for signs and symptoms of myopathy and/or rhabdomyolysis.
    Regadenoson: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with erythromycin include regadenoson.
    Repaglinide: (Moderate) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Clarithromycin inhibits this enzyme and has been found to produce a greater hypoglycemic effect from repaglinide. These are clinically significant increases in repaglinide plasma levels which may necessitate a repaglinide dose adjustment. Erythromycin is likely to interact in a similar fashion.
    Ribociclib: (Major) Avoid coadministration of ribociclib with erythromycin due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Erythromycin is also associated with QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and erythromycin is a moderate CYP3A4 inhibitor. Additionally, ribociclib is a moderate CYP3A4 inhibitor and erythromycin is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with erythromycin due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Erythromycin is also associated with QT prolongation and TdP. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and erythromycin is a moderate CYP3A4 inhibitor. Additionally, ribociclib is a moderate CYP3A4 inhibitor and erythromycin is a CYP3A4 substrate.
    Rifabutin: (Severe) Erythromycin is a substrate and inhibitor of CYP3A4, and rifabutin is a substrate and inducer of CYP3A4. It is likely that erythromycin will inhibit the metabolism of rifabutin, resulting in significant increases in rifabutin serum concentrations and adverse reactions. Rifabutin may also induce the metabolism of erythromycin, resulting in decreased erythromycin concentrations thereby reducing the antimicrobial efficacy of erythromycin.
    Rifampin: (Major) Erythromycin is a substrate and inhibitor of CYP3A4, and rifampin is an inducer of CYP3A4. Coadministration of oral erythromycin 500 mg and rifampin 600 mg to healthy patients led to a reduced erythromycin maximum serum concentration (Cmax) and an increased clearance. Specifically, as monotherapy, the median erythromycin Cmax was 1.34 mg/L (range, 0.4 to 3.16), and the median apparent oral clearance was 96 L/hour (range, 37 to 250). In combination with rifampin, the median erythromycin Cmax was 0.72 mg/L (range, 0.06 to 1.66), and the median apparent oral clearance was 197 L/hour (range, 102 to 2015).
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and erythromycin, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin 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 erythromycin.
    Risperidone: (Major) Concurrent use of risperidone and erythromycin should generally be avoided because risperidone has been associated with a possible risk of QT prolongation and torsade de pointes and erythromycin has a causal association with these effects. In addition, pharmacokinetic data indicate that increased exposure to risperidone and its active metabolite occurs during use of erythromycin. This interaction is thought to be the result of inhibition of CYP3A4, one of the isoenzymes responsible for the metabolism of risperidone.
    Ritonavir: (Major) Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
    Rivaroxaban: (Moderate) Coadministration of rivaroxaban and erythromycin may result in increases in rivaroxaban exposure. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of single-dose rivaroxaban and erythromycin, a combined P-gp and moderate CYP3A4 inhibitor, led to increases in the rivaroxaban AUC and Cmax by 30% in adult patients with normal renal function. A single dose of rivaroxaban was administered to patients wtih mild (CrCl 50 to 79 ml/min) or moderate (CrCl 30 to 49 ml/min) renal dysfunction receiving multiple doses of erythromycin. Compared to rivaroxaban administered alone to patients with normal renal function, patients with mild and moderate renal dysfunction reported a 76% and 99% increase in rivaroxaban AUC and a 56% and 64% increase in rivaroxaban Cmax, respectively. Significant increases in rivaroxaban exposure may increase bleeding risk. However, while an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)]. According to the manufacturer of rivaroxaban, when clinical data suggest the change in exposure is unlikely to affect bleeding risk (e.g., erythromycin), no precautions are necessary during coadministration. More generally, coadministration of rivaroxaban with other combined CYP3A4 and moderate P-gp inhibitors is to be avoided in patients with CrCl 15 to 80 ml/min unless the potential benefit justifies the potential risk.
    Roflumilast: (Moderate) Coadminister erythromycin and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Erythromycin is a strong CYP3A4 inhibitor; roflumilast is a CYP3A4 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of erythromycin (500 mg three times daily for 13 days) with a single oral dose of roflumilast 500 mcg resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease in Cmax and a 4% increase AUC for the active metabolite roflumilast N-oxide.
    Romidepsin: (Major) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Erythromycin is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. In addition, romidepsin has been reported to prolong the QT interval. Erythromycin may also prolong the QT interval. If romidepsin and erythromycin must be continued, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Rosuvastatin: (Minor) Erythromycin is generally associated with an increased risk of myopathy with HMG-CoA reductase inhibitors. This interaction is likely due to CYP3A4 inhibition of statins which are CYP3A4 substrates (e.g., cerivastatin, lovastatin, simvastatin, atorvastatin). Rosuvastatin is not substantially metabolized, and is less likely to be significantly affected by CYP3A4 inhibitors such as erythromycin. Coadministration of a single dose of rosuvastatin (80 mg) with erythromycin results in 31% and 20% decrease in Cmax and AUC of rosuvastatin, respectively. The clinical significance of this interaction has not been established.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as erythromycin, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Salmeterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists, like salmeterol. Additionally, salmeterol is a CYP3A4 substrates, and erythromycin, a CYP3A4 inhbitor, may increase salmeterol concentrations. A small study of 13 healthy subjects resulted in a 40% increase in salmeterol maximum concentrations (Cmax) during concurrent repeat-dose administration of erythromycin. The QT interval increased by 5.8 msec and a small, but statistically significant increase in heart rate occurred (3.6 beats/minute). No dose adjustment is suggested, but caution is advised. The effects of salmeterol on the cardiovascular system, as well as side effects like headache, tremor, and nervousness, may be potentiated.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and erythromycin as coadministration may result in increased systemic exposure of erythromycin. Erythromycin is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of erythromycin.
    Saquinavir: (Severe) Concurrent use of erythromycin and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and erythromycin are inhibitors and substrates of the hepatic isoenzyme CYP3A4 as well as the drug efflux pump, P-glycoprotein (P-gp). This complex interaction may ultimately result in altered plasma concentrations of both erythromycin and saquinavir. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as erythromycin.
    Saxagliptin: (Minor) Saxagliptin plasma concentrations are expected to increase in the presence of moderate CYP 3A4/5 inhibitors such as erythromycin, but saxagliptin dose adjustment is not advised.
    Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include erythromycin.
    Short-acting beta-agonists: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Sibutramine: (Moderate) The hepatic CYP450 3A4-mediated metabolism of sibutramine may be inhibited by erythromycin.
    Sildenafil: (Major) Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as erythromycin: 25 mg/day PO, approximately 1 hour prior to sexual activity. When a single 100 mg dose of sildenafil is administered with erythromycin (500 mg bid for 5 days), a specific CYP3A4 inhibitor, at steady state, there is a 182% increase in sildenafil systemic exposure (AUC). In vivo studies of healthy male volunteers show no clinically significant effect of azithromycin (500 mg PO daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.
    Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4 and is a substrate for P-glycoprotein (P-gp). In theory, drugs that inhibit CYP3A4 and P-gp such as erythromycin may cause significant increases in silodosin plasma concentrations.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and erythromycin; consider use of azithromycin in place of erythromycin. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by both drugs results in increased plasma concentrations of simeprevir by 647% and erythromycin by 90%. Administering these drugs together may result in adverse effects.
    Simvastatin: (Severe) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Simvastatin; Sitagliptin: (Severe) Erythromycin is contraindicated during simvastatin therapy. Erythromycin potently inhibits the metabolism of simvastatin via the CYP3A4 isoenzyme and increases the risk of myopathy and rhabdomyolysis. According to the manufacturer, if no alternative to a short course of erythromycin therapy is available, therapy with simvastatin must be suspended during the course of erythromycin treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by erythromycin. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of results.
    Sirolimus: (Major) Avoid the use of sirolimus with strong CYP3A4 inhibitors, such as erythromycin. Erythromycin may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein (P-gp) drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4. In 24 healthy volunteers, sirolimus Cmax and AUC were increased by 4.4- and 4.2-fold respectively, with simultaneous oral administration of sirolimus oral solution (2 mg PO) and erythromycin ethylsuccinate tablets (800 mg every 8 hours). Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold. Additionally, sirolimus is a substrate for P-gp, and erythromycin is a P-gp inhibitor.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with erythromycin. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, erythromycin is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and erythromycin. Taking these medications together may increase plasma concentrations of both drugs, potentially increasing the risk for adverse events. Voxilaprevir is a substrate for the drug transporter Organic Anion Transporting Polypeptides 1B1/1B3 (OATP1B1/1B3); erythromycin is an OATP1B1/1B3 inhibitor. In addition, voxilaprevir is an inhibitor of P-glycoprotein, while erythromycin is a P-gp substrate. (Moderate) Use caution when administering velpatasvir with erythromycin. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, erythromycin is an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Solifenacin: (Major) Solifenacin is significantly metabolized via the CYP3A4 pathway. Patients receiving CYP3A4 inhibitors, such as erythromycin, should not receive solifenacin doses greater than 5 mg per day. In addition, solifenacin is associated with dose-dependent QT prolongation, and torsades de pointes (TdP) has been reported with post-marketing use. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP) and should be used cautiously and with close monitoring with solifenacin. Also solifenacin may antagonize the stimulatory effects of erythromycin on the GI tract when erythromycin is used therapeutically for improving GI motility. If erythromycin is not being used to enhance GI motility, then these potential interactions are of little clinical significance.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and erythromycin; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and erythromycin is a moderate CYP3A4 inhibitor. If concomitant use cannot be avoided, administer the moderate CYP3A inhibitor for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 1.8-fold in cancer patients who received 14 days of sonidegib 200 mg/day and a moderate CYP3A4 inhibitor (i.e., erythromycin). Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would increase 2.8-fold in cancer patients who received sonidegib 200 mg/day and a moderate CYP3A4 inhibitor (i.e., erythromycin) for 4 months.
    Sorafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with sorafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Erythromycin is associated with prolongation of the QT interval and TdP. Sorafenib has also been associated with QT prolongation. Additionally, erythromycin concentrations may increase with coadministration of sorafenib as erythromycin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro.
    Sotalol: (Major) Concurrent use of erythromycin with Class III (amiodarone, ibutilide, sotalol) antiarrhythmic agents should be avoided. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). In addition to potential pharmacokinetic interactions, erythromycin may cause QT prolongation and exhibit additive electrophysiologic effects with Class III antiarrhythmics. Sotalol administration is associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Soy Isoflavones: (Minor) Bacteria in the intestine produce enzymes which hydrolyze the soy isoflavones to the active isoflavonoids genistein and daidzein; alterations in gut microflora have been correlated with effects on soy isoflavone bioavailability. Macrolides significantly reduce the GI microflora and could theoretically prevent the formation of the active components of the soy isoflavones.
    Sparfloxacin: (Severe) Sparfloxacin is associated with an established risk for QT prolongation and torsades de pointes and is contraindicated in patients receiving these drugs or other drugs that can cause QT prolongation including erythromycin.
    St. John's Wort, Hypericum perforatum: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by this enzyme, such as erythromycin. Clinicians should observe patients closely if St. John's wort is used.
    Streptogramins: (Moderate) Streptogramins are major inhibitors of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including erythromycin.
    Sufentanil: (Moderate) Sufentanil is metabolized by the cytochrome P450 3A4 isoenzyme. Agents that inhibit CYP3A4 activity, such as erythromycin, may decrease systemic clearance of sufentanil leading to increased or prolonged effects. Close monitoring for oversedation is warranted in these patients.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include erythromycin.
    Sunitinib: (Major) Concurrent administration of sunitinib with inhibitors of cytochrome P450 3A4 such as erythromycin results in increased concentrations of sunitinib and its primary active metabolite. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended. If an alternative therapy is not available, monitor patients closely for increased adverse reactions to sunitinib; a reduction in the dose of sunitinib may be required. In addition, erythromycin has an established risk for QT prolongation and torsades de pointes (TdP). Use sunitinib and erythromycin together with caution due to the risk of additive QT prolongation.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors such as erythromycin and a maximum recommended dose of 10 mg/day.
    Tacrolimus: (Major) When possible avoid concurrent erythromycin and tacrolimus therapy. However, if concomitant therapy is necessary, close monitoring of tacrolimus blood concentrations and of the QT interval is warranted. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP such as tacrolimus should be used cautiously with erythromycin. In addition, the concurrent administration of erythromycin and tacrolimus may result in elevated tacrolimus levels resulting in nephrotoxicity. In one case, the whole blood tacrolimus concentration was > 60 ng/ml following 3 days of therapy with erythromycin (prior tacrolimus level 9.8 ng/ml).
    Tadalafil: (Major) Avoid coadministration of erythromycin and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of erythromycin for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as ketoconazole, may reduce tadalafil clearance. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as erythromycin, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
    Tamoxifen: (Major) Concomitant use of tamoxifen and erythromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Erythromycin is associated with QT prolongation and TdP. Erythromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as erythromycin. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and erythromycin. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as erythromycin, may increase exposure to tasimelteon with the potential for adverse reactions.
    Telaprevir: (Major) Close clinical monitoring is advised when administering clarithromycin with telaprevir due to an increased potential for serious erythromycin-related adverse events, such as QT prolongation and torsade de pointes (TdP). Predictions about the interaction can be made based on the metabolic pathways of erythromycin and telaprevir. Both erythromycin and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug efflux transporter, P-glycoprotein (P-gp). When used in combination, the plasma concentrations of both medications may be elevated. Monitor for evidence of interactions. If erythromycin dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.
    Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with erythromycin. Both telavancin and erythromycin have been associated with QT prolongation, while erythromycin is also associated with cases of TdP.
    Telbivudine: (Moderate) The risk of myopathy may be increased if erythromycin is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with telithromycin. Both telithromycin and erythromycin are associated with prolongation of the QT interval and TdP. Additionally, telithromycin is a strong inhibitor of CYP3A4, while erythromycin is a substrate and inhibitor of this enzyme.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and erythromycin is necessary, as the systemic exposure of erythromycin may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of erythromycin as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of erythromycin if necessary. Erythromycin is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and erythromycin is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with erythromycin is necessary, and monitor for an increase in temsirolimus- and erythromycin-related adverse reactions. Temsirolimus is a CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of moderate inhibitors. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Coadministration of erythromycin with sirolimus increased the sirolimus Cmax and AUC by 4.4-fold and 4.2-fold, respectively. Additionally, temsirolimus is an in vitro substrate/inhibitor of P-glycoprotein (P-gp) and erythromycin is also a P-gp substrate/inhibitor. Concomitant use may result in increased plasma concentrations of both erythromycin and temsirolimus (and active metabolite, sirolimus).
    Tenofovir Alafenamide: (Moderate) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with erythromycin. Use of these drugs together may result in elevated tenofovir plasma concentrations. When possible, an alternative antibiotic such as azithromycin should be considered. Erythromycin is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering erythromycin. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; erythromycin is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Terbutaline: (Minor) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the beta-agonists. The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Tetrabenazine: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Tetrabenazine causes a small increase in the corrected QT interval. The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as erythromycin.
    Theophylline, Aminophylline: (Major) Erythromycin can inhibit aminophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. If erythromycin is used with aminophylline therapy, patients should be monitored for elevated theophylline levels and/or toxicity. (Major) Erythromycin can inhibit theophylline clearance by inhibiting the cytochrome P450 CYP3A isoenzymes. If erythromycin is used with theophylline therapy, patients should be monitored for elevated theophylline levels and/or theophylline toxicity.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with erythromycin which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and erythromycin may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tiotropium; Olodaterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). Erythromycin, a dual moderate CYP3A4 and a P-gp inhibitor, might increase olodaterol drug concentrations. Coadministration of olodaterol inhalation with a strong CYP3A4/P-gp dual inhibitor resulted in a 1.7-fold increase in olodaterol AUC. No dose adjustment is suggested, but caution is advised. The effects of olodaterol on the cardiovascular system, and side effects like headache, tremor, or nervousness may be potentiated.
    Tizanidine: (Major) Tizanidine should be used cautiously and with close monitoring with erythromycin. Tizanidine administration may result in QT prolongation. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tolterodine: (Major) Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Tolterodine should be used cautiously and with close monitoring in patients taking erythromycin. Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Furthermore, patients receiving strong CYP3A4 inhibitors, such as erythromycin, concomitantly with tolterodine should not receive > 2 mg/day of tolterodine. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive > 2 mg/day of tolterodine. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Erythromycin is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increase in tolvaptan concentrations and should be avoided.
    Topotecan: (Major) Avoid the concomitant use of erythromycin, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of erythromycin and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea; this also applies to combination products containing erythromycin, including erythromycin; sulfisoxazole. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include erythromycin.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and erythromycin is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tramadol: (Moderate) Administration of CYP3A4 inhibitors such as erythromycin with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Trandolapril; Verapamil: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Trazodone: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Erythromycin has a possible risk for QT prolongation and TdP. In addition, erythromycin could impair the metabolism of trazodone through inhibition of CYP3A4, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    Tretinoin, ATRA: (Moderate) Erythromycin may decrease the CYP450 metabolism of tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA. No specific studies have been done with oral tretinoin and erythromycin, however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy.
    Triazolam: (Major) Erythromycin can inhibit the hepatic metabolism of other drugs, such as triazolam, increasing their serum concentrations and potentially causing toxicity.
    Tricyclic antidepressants: (Minor) The use of erythromycin with tricyclic antidepressants is rarely problematic. Tricyclic antidepressants may prolong the QT interval, particularly in overdose, and erythromycin has also been reported to have this effect in rare circumstances. Erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some tricyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin's effectiveness.
    Trifluoperazine: (Minor) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with trifluoperazine. Erythromycin is associated with prolongation of the QT interval and TdP. Trifluoperazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Trimetrexate: (Moderate) Erythromycin can inhibit oxidative hepatic enzymes responsible for metabolizing trimetrexate. Concurrent use can decrease the clearance of trimetrexate and thus increase its plasma levels. Use this combination with caution.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include erythromycin.
    Trospium: (Minor) The antimuscarinics can antagonize the stimulatory effects of erythromycin on the GI tract when erythromycin is used therapeutically for improving GI motility.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and erythromycin is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Umeclidinium; Vilanterol: (Moderate) Erythromycin administration is associated with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with erythromycin include the long-acting beta-agonists (LABAs). The effects of these beta-agonists on the cardiovascular system may be potentiated. Beta agonists infrequently produce cardiovascular adverse effects, mostly with high doses or in the setting of beta-agonist-induced hypokalemia.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; erythromycin also has a possible risk for QT prolongation and TdP. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. Additionally, erythromycin is partially a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of another P-gp substrate by 29% and 23%, respectively; exposure to erythromycin may also increase. Finally, erythromycin is also a moderate CYP3A4 inhibitor. While strong CYP3A4 inducers affect serum concentrations of both vandetanib and its active metabolite, N-desmethyl-vandetanib, erythromycin is not expected to affect vandetanib exposure based on a crossover study (n = 14) in which no clinically significant interaction was noted between vandetanib and a strong CYP3A4 inhibitor.
    Vardenafil: (Major) It may be prudent to avoid the use of vardenafil in patients being treated with erythromycin. If these drugs must be used together, do so with extreme caution. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Erythromycin is generally considered by experts to have an established risk for QT prolongation and torsades de pointes (TdP). Vardenafil, at therapeutic (10 mg) and supratherapeutic (80 mg) doses, produces increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). Coadministration could lead to the risk of additive QT prolongation. Additionally, erythromycin inhibits CYP3A4. Vardenafil is metabolized by CYP3A4. Coadministration of erythromycin (500 mg tid) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively; increased vardenafil concentrations further increase the risk for serious side effects.
    Vemurafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both erythromycin and vemurafenib have been associated with QT prolongation. Also, erythromycin is a CYP3A4 substrate/inhibitor and a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. Concentrations of both erythromycin and vemurafenib may be altered with concomitant use.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and erythromycin; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and erythromycin is a CYP3A4 (moderate) and P-gp inhibitor. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If erythromycin is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    Venlafaxine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with venlafaxine. Erythromycin is associated with prolongation of the QT interval and TdP. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has reported with post-marketing use.
    Verapamil: (Major) Avoid administration of erythromycin and a calcium-channel blocker, particularly in geriatric patients. Coadministration has been associated with an increased risk of hypotension and shock. Azithromycin may be preferred if the use of a macrolide antibiotic is necessary in a patient receiving calcium-channel blocker therapy. Erythromycin may also decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Concurrent use of erythromycin with diltiazem and verapamil has been associated with sudden cardiac death. This interaction is likely due to the combined inhibition of CYP3A by erythromycin and the calcium channel blockers leading to increases in the serum concentrations of erythromycin and the calcium channel blockers.
    Vinblastine: (Severe) Erythromycin may inhibit the metabolism and/or drug efflux of vinblastine. Three patients developed severe vinblastine toxicity during erythromycin coadministration that responded to dechallenge and reappeared with rechallenge. Erythromycin is known to inhibit P-glycoprotein, an energy-dependent drug-efflux pump, which is found in many normal tissues including bone marrow cells. Until more data are available, clinicians should avoid erythromycin in patients receiving vinblastine.
    Vincristine Liposomal: (Major) Erythromycin inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is both a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Major) Erythromycin inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is both a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vinorelbine: (Moderate) Use caution and monitor patients for an earlier onset and/or an increased severity of adverse effects, including neurotoxicity and myelosuppression, if erythromycin is used concomitantly with vinorelbine. Erythromycin is a CYP3A4 inhibitor and vinorelbine is a CYP3A4 substrate; coadministration may cause the metabolism of vinorelbine to be decreased. This also applies to combination products containing erythromycin, such as erythromycin; sulfisoxazole.
    Vitamin C: (Moderate) Monitor for decreased efficacy of erythromycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration may result in decreased efficacy of erythromycin.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and erythromycin. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with erythromycin, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as erythromycin. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4. Both erythromycin and voriconazole are associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration could result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. However, in one study, no significant effects on voriconazole plasma concentrations were observed following concurrent administration of erythromycin 1 g every 12 hours for 7 days with voriconazole 200 mg every 12 hours for 14 days; the effects of voriconazole on the pharmacokinetics of erythromycin are not known. A retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors (nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin) increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Major) Erythromycin administration is associated with QT prolongation and torsades de pointes (TdP). Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with erythromycin.
    Warfarin: (Moderate) Erythromycin inhibits warfarin hepatic clearance, and concomitant use with warfarin can increase INR values. The INR should be monitored carefully if erythromycin is added to warfarin therapy. If warfarin is added after erythromycin therapy has begun, no special precautions appear to be necessary, however, if erythromycin is subsequently discontinued, warfarin dosages may need to be adjusted. Interactions between erythromycin and warfarin may be more pronounced in elderly patients.
    Zafirlukast: (Moderate) Erythromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when erythromycin is added concurrently.
    Zaleplon: (Minor) Erythromycin may increase the serum concentrations of zaleplon through CYP3A4 inhibition.
    Zileuton: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4. Although administration of zileuton with other drugs metabolized by CYP3A4 has not been studied, zileuton may inhibit CYP3A4 isoenzymes. Zileuton could potentially compete with other CYP3A4 substrates, including erythromycin.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including erythromycin.
    Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of erythromycin, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and erythromycin is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    Erythromycin is classified in FDA pregnancy category B. Data available from human use during pregnancy do not support an association with erythromycin use and congenital malformations. Erythromycin crosses the placenta, but in low concentrations. One salt form, erythromycin estolate, has been observed to produce hepatotoxicity in pregnant patients. Roughly 10% of pregnant women treated with erythromycin estolate have abnormal, elevated hepatic enzymes during treatment. In most cases, the transaminases return to normal levels upon discontinuation of therapy. When pregnant women are treated with erythromycin, a formulation other than the estolate salt is recommended.

    According to the manufacturer, erythromycin should be used with caution in breast-feeding mothers because it is excreted into breast milk. A prospective observational study assessing the safety of macrolide antibiotics during lactation found that 12.7% (n = 55) of babies exposed to macrolides via breast milk experienced adverse events including rash, diarrhea, loss of appetite, and somnolence. The adverse event rate was similar to that seen in babies in a control group whose mothers were treated with amoxicillin (8.3%). Only  2 mothers in the study received erythromycin, 10 received azithromycin, 6 received clarithromycin, and the remainder were treated with roxythromycin. A population based cohort study found that babies diagnosed with infantile hypertrophic pyloric stenosis were 2.3—3 times more likely to have been exposed to a macrolide antibiotic through breast milk during the first 90 days of life than babies not exposed during that same time period. The study did not specify which antibiotic the mothers of affected babies were prescribed; however, the majority of macrolide prescriptions were for erythromycin (72%), with 7% for azithromycin and 1.7% for clarithromycin. The American Academy of Pediatrics (AAP) considers erythromycin to be a medication that is usually compatible with breast-feeding; azithromycin and clarithromycin have not been evaluated by the AAP. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Erythromycin binds to the 50S ribosomal subunit, inhibiting bacterial protein synthesis. It is effective against a wide range of microorganisms, and like other antibiotics that inhibit protein synthesis, is mainly bacteriostatic. Activity against gram-positive organisms generally is greater than against gram-negative organisms due to its superior penetration into gram-positive organisms. The primarily mechanisms for bacterial resistance to erythromycin include a modification of the 23S rRNA in the 50S ribosomal subunit and drug efflux.
     
    Erythromycin also has actions that make it useful outside of the infectious disease field. It mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility. This action is probably due to binding at the motilin receptors. Motilin receptors are found mainly in the gastric antrum and proximal duodenum. The physiologic action produced is an increased motility during the interdigestive (between-meal) period, without affecting postprandial motility. Erythromycin does not affect either dopamine receptors or increase acetylcholine concentrations in the gut. Tachyphylaxis can result from motilin receptor downregulation.

    PHARMACOKINETICS

    Erythromycin is administered orally, intravenously, topically, and ophthalmically.
     
    Distribution is extensive following either oral or parenteral administration. Protein binding is 73—81%; the estolate salt is 96% bound. Erythromycin crosses the placenta and is distributed into breast milk. Only small amounts penetrate the CSF. Except for the brain, tissue concentrations persist longer than do serum concentrations. Erythromycin concentrates in the bile and liver in patients with normal hepatic function. Levels in semen and prostatic fluid are about 33% higher than in serum. Because of its' relatively poor oral absorption, significant concentrations are achieved in the large intestine.
     
    Erythromycin is metabolized in the liver to several inactive metabolites; it is a substrate and inhibitor of the CYP3A4 enzyme system and of P-glycoprotein. Excretion is mainly via the bile, with some reabsorption. Only small amounts are found in the urine. In patients with normal renal function, the serum half-life is about 1.5—2 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
    Erythromycin is a substrate and inhibitor of the CYP3A4 enzyme system and of P-glycoprotein.

    Oral Route

    In general, oral bioavailability of erythromycin is poor. Erythromycin is readily inactivated by stomach acid, and several salts have been developed to overcome this drawback. Absorption takes place mainly in the duodenum. Gastric emptying time, the salt or formulation administered, and the presence of food in the stomach also affect bioavailability, especially for the unprotected base. Stearate preparations are susceptible to gastric acid destruction; however, dissociation in the duodenum yields free erythromycin, which is subsequently absorbed. Estolate preparations are more acid-stable and dissociate in the upper intestine to liberate an inactive propanoate ester, which is then absorbed and hydrolyzed in the blood to produce free erythromycin. Ethylsuccinate preparations are absorbed first and hydrolyzed in the blood to free erythromycin. The newest formulation of oral erythromycin is encapsulated pellets that are small enough to pass through the pyloric sphincter independent of gastric emptying and are absorbed as the base. None of the oral forms, however, allows complete absorption, although some evidence suggests oral bioavailability is greatest with the oral pellets.
     
    All oral dosage forms produce relatively similar effective erythromycin base serum concentrations, although some data suggest the erythromycin base serum concentrations are somewhat higher after oral doses of the estolate salt compared to the ethylsuccinate. Following single oral doses, peak serum levels of free erythromycin are achieved in 1—4 hours and range from 0.1—2 mcg/mL.

    Intravenous Route

    Parenteral erythromycin is available as the gluceptate or lactobionate. Since administration of parenteral erythromycin is painful, these preparations are used when high serum levels of erythromycin are desirable. Serum levels of 8—12 mcg/mL are possible after IV doses of 500—1000 mg.