(er ith roe MYE sin)
Bacterial infections: Treatment of susceptible bacterial infections, including S. pyogenes, some S. pneumoniae, some S. aureus, M. pneumoniae, Legionella pneumophila, diphtheria, pertussis, Chlamydia, erythrasma, N. gonorrhoeae, E. histolytica, syphilis and nongonococcal urethritis, and Campylobacter gastroenteritis; used in conjunction with neomycin for decontaminating the bowel
Surgical (preoperative) prophylaxis (colorectal): Colorectal decontamination, in conjunction with other agents, prior to surgical intervention
Hypersensitivity to erythromycin, any macrolide antibiotics, or any component of the formulation
Concomitant use with pimozide, cisapride, ergotamine or dihydroergotamine, terfenadine, astemizole, lovastatin, or simvastatin
Note: Due to differences in absorption, 400 mg erythromycin ethylsuccinate produces the same serum levels as 250 mg erythromycin base or stearate.
Usual dosage range:
Oral:
Base: 250 to 500 mg every 6 to 12 hours; maximum: 4 g daily
Ethylsuccinate: 400 to 800 mg every 6 to 12 hours; maximum: 4 g daily
IV: Lactobionate: 15 to 20 mg/kg/day divided every 6 hours or 500 mg to 1 g every 6 hours; maximum: 4 g daily
Indication-specific dosing:
Bartonella spp infections (bacillary angiomatosis [BA], peliosis hepatis [PH]) (off-label use): Oral: 500 mg (base) 4 times daily for 3 months (BA) or 4 months (PH) (Koehler 1992; Rolain 2004; Stevens 2014; Tappero 1993). Note: IDSA skin and soft tissue infection guidelines recommend a duration of initial therapy of 2 weeks to 2 months for cutaneous BA, although treatment durations are not standardized (IDSA [Stevens 2014])
Bartonellaspp infections in HIV-infected patients (off-label use; HHS [OI adult 2015]):Note: Duration of therapy is at least 3 months; continuation of therapy depends on relapse occurrence and clinical condition
Bacillary angiomatosis, peliosis hepatis, bacteremia, and osteomyelitis: Oral, IV: 500 mg every 6 hours
Other severe infections (excluding CNS infections or endocarditis): Oral, IV: 500 mg every 6 hours with rifampin
Chancroid (off-label use): Oral: 500 mg (base) 3 times daily for 7 days; Note: Isolates with intermediate resistance have been documented ( CDC [Workowski 2015])
Chlamydia trachomatis infection, uncomplicated: Oral:
Manufacturer 's labeling: Urethral, endocervical, or rectal infections (when tetracycline is contraindicated or not tolerated): 500 mg (base) 4 times a day or two 333 mg (base) tablets every 8 hours for at least 7 days
Alternate dosing; Urogenital infections: 500 mg (base) four times daily or 800 mg (ethylsuccinate) four times daily for 7 days (CDC [Workowski 2015])
Gastroparesis (off-label use):
IV: 3 mg/kg administered over 45 minutes every 8 hours (Camilleri 2013)
Oral: Patients refractory/intolerant to other prokinetic agents (eg, metoclopramide, domperidone): 250 to 500 mg (base) 3 times daily before meals. Limit duration of therapy, tachyphylaxis may occur after 4 weeks (Camilleri 2013).
Granuloma inguinale (donovanosis) (off-label use): Oral: 500 mg (base) 4 times daily for at least 21 days and resolution of lesions (CDC [Workowski 2015]). Note: If symptoms do not improve within the first few days of therapy, the addition of gentamicin may be considered (CDC [Workowski 2015]).
Impetigo (IDSA [Stevens 2014]): Oral:
Base: 250 mg 4 times daily for 7 days, depending on response
Ethylsuccinate: 400 mg 4 times daily for 7 days, depending on response
Legionnaire disease: Oral: 1.6 to 4 g (ethylsuccinate) daily or 1 to 4 g (base) daily in divided doses for 21 days. Note: No longer preferred therapy and only used in nonhospitalized patients.
Lymphogranuloma venereum (alternative to preferred therapy) (off-label use): Oral: 500 mg (base) 4 times daily for 21 days (CDC [Workowski 2015])
Nongonococcal urethritis: Oral:
Manufacturer 's labeling:
Base: When tetracycline is contraindicated or not tolerated: 500 mg (base) 4 times daily or two 333 mg (base) tablets every 8 hours for at least 7 days
Ethylsuccinate: 800 mg (ethylsuccinate) 3 times daily for 7 days. Note: May use 250 mg (base) or 400 mg (ethylsuccinate) 4 times daily for 14 days if gastrointestinal intolerance.
Alternate dosing: 500 mg (base) 4 times daily or 800 mg (ethylsuccinate) 4 times daily for 7 days (CDC [Workowski 2015]).
Pertussis: Oral: 500 mg (base) every 6 hours for 14 days
Surgical (preoperative) prophylaxis (colorectal) (off-label dose): Oral: 1 g erythromycin base per dose at 1 PM, 2 PM, and 11 PM on the day before 8 AM surgery combined with mechanical cleansing of the large intestine, oral neomycin. Perioperative IV antibiotics are also given on the day of surgery (Bratzler 2013).
Refer to adult dosing.
Note: Due to differences in absorption, 400 mg erythromycin ethylsuccinate produces the same serum levels as 250 mg erythromycin base or stearate.
Usual dosage range: Infants and Children:
Oral:
Base: 30 to 50 mg/kg/day in 2 to 4 divided doses; maximum: 2 g daily
Ethylsuccinate: 30 to 50 mg/kg/day in 2 to 4 divided doses; dose may be increased (eg, to 60 to 100 mg/kg/day) in severe infections; maximum: 4 g/day
Stearate: 30 to 50 mg/kg/day in 2 to 4 divided doses; maximum: 2 g daily
IV: Lactobionate: 15 to 20 mg/kg/day divided every 6 hours; maximum: 4 g daily
Indication-specific dosing:
Infants and Children:
Bartonella spp infections (bacillary angiomatosis [BA], peliosis hepatis [PH]) (off-label use): Oral: 40 mg/kg/day (ethylsuccinate) in 4 divided doses (maximum: 2 g daily) for 3 months (BA) or 4 months (PH) (Rolain 2004). Note: IDSA skin and soft tissue infection guidelines recommend a duration of initial therapy of 2 weeks to 2 months for cutaneous BA, although treatment durations are not standardized (IDSA [Stevens 2014])
Chlamydia trachomatisinfection, uncomplicated: Urogenital infection:
Children and Adolescents <45 kg (off-label population): 50 mg/kg/day (base or ethylsuccinate) in 4 divided doses for 14 days (CDC [Workowski 2015])
Adolescents ≥45 kg (off-label population): 500 mg (base) four times daily or 800 mg (ethylsuccinate) four times daily for 7 days (CDC [Workowski 2015])
Community-acquired pneumonia (CAP) (IDSA/PIDS 2011): Infants >3 months and Children: Note: A beta-lactam antibiotic should be added if typical bacterial pneumonia cannot be ruled out.
Presumed atypical (M. pneumoniae, Chlamydophila [also known as Chlamydia] pneumoniae, C. trachomatis) infection, mild atypical infection or step-down therapy (alternative to azithromycin): Oral: 10 mg/kg/dose every 6 hours
Moderate to severe atypical infection (alternative to azithromycin): IV: 5 mg/kg/dose every 6 hours
Impetigo: Oral: 40 mg/kg/day in 3 to 4 divided doses for 7 days, depending on response (IDSA [Stevens 2014])
Mild/moderate infection: Oral: 30 to 50 mg/kg/day in divided doses every 6 to 12 hours
Pertussis: Oral: 40 to 50 mg/kg/day in 4 divided doses for 14 days; maximum: 2 g daily (not preferred agent for infants <1 month due to IHPS)
Pharyngitis, tonsillitis (streptococcal): Oral: 20 mg (base)/kg/day or 40 mg (ethylsuccinate)/kg/day in 2 divided doses for 10 days. Note: No longer preferred therapy due to increased organism resistance.
Surgical (preoperative) prophylaxis (colorectal) (off-label use): Children ≥1 year: Oral: 20 mg (base)/kg (maximum dose: 1000 mg) at 1 PM, 2 PM, and 11 PM on the day before 8 AM surgery combined with mechanical cleansing of the large intestine, oral neomycin. Perioperative IV antibiotics are also given on the day of surgery (Bratzler 2013).
Severe infection: IV: 15 to 20 mg/kg/day divided every 6 hours; maximum: 4 g daily
Adolescents:
Bartonellaspp infections in HIV-infected patients (off-label use): Refer to adult dosing.
There are no dosage adjustments provided in the manufacturers labeling.
Dialysis: Slightly dialyzable (5% to 20%). Supplemental dose is not necessary in hemo- or peritoneal dialysis or in continuous arteriovenous or venovenous hemofiltration (Aronoff 2007).
There are no dosage adjustments provided in the manufacturers labeling; use with caution.
Erythromycin lactobionate should be reconstituted with sterile water for injection without preservatives to a concentration of 50 mg/mL. No less than 100 mL of IV diluent should be used for an infusion bag. The final diluted solution should be 1 to 5 mg/mL.
Oral: Administer base, PCE or stearate dosage forms on an empty stomach (2 hours before or after a meal); administer ethylsuccinate (EES) or delayed-release (ERY-TAB) without regards to meals; may consider administering after food to decrease GI discomfort. Swallow delayed release capsule or enteric coated tablets whole, do not chew or break.
IV: Infuse 1 g over 20 to 60 minutes. IV infusion may be very irritating to the vein; infusion should be sufficiently slow to minimize pain along the vein. Do not administer IV push or bolus.
Some products may contain sodium.
Base, PCE or stearate dosage forms should be taken on an empty stomach (2 hours before or after a meal).
Ethylsuccinate (EES) or delayed-release (ERY-TAB) dosage forms may be administered without regards to meals.
May consider administering after food to decrease GI discomfort.
Injection: Store unreconstituted vials at 20 � �C to 25 � �C (68 � �F to 77 � �F). Reconstituted solution (50 mg/mL) is stable for 2 weeks when refrigerated or for 24 hours at room temperature. Erythromycin IV infusion solution is stable at pH 6 to 8; stability of lactobionate is pH dependent; IV form has longest stability in NS. Parenteral admixture in NS is stable for 24 hours at 4 � �C. Admixtures in NS (including Add-Vantage containers) should be infused within 8 hours of preparation.
Oral suspension:
Granules: Prior to mixing, store at 20 � �C to 25 � �C (68 � �F to 77 � �F). After mixing, store under refrigeration and use within 10 days.
Powder: Prior to mixing, store at <30 � �C (86 � �F). After mixing, store at ≤25 � �C (77 � �F) and use within 35 days.
Tablet and capsule formulations: Store at 20 � �C to 25 � �C (68 � �F to 77 � �F).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Delayed Release Particles, Oral, as base:
Generic: 250 mg
Solution Reconstituted, Intravenous, as lactobionate:
Erythrocin Lactobionate: 500 mg (1 ea); 1000 mg (1 ea [DSC])
Suspension Reconstituted, Oral, as ethylsuccinate:
E.E.S. Granules: 200 mg/5 mL (100 mL, 200 mL) [cherry flavor]
EryPed 200: 200 mg/5 mL (100 mL) [fruit flavor]
EryPed 400: 400 mg/5 mL (100 mL) [banana flavor]
Tablet, Oral, as base:
Generic: 250 mg, 500 mg
Tablet, Oral, as ethylsuccinate:
E.E.S. 400: 400 mg [contains fd&c red #40, fd&c yellow #10 (quinoline yellow)]
Generic: 400 mg
Tablet, Oral, as stearate:
Erythrocin Stearate: 250 mg
Tablet Delayed Release, Oral, as base:
Ery-Tab: 250 mg, 333 mg, 500 mg
PCE: 333 mg
PCE: 500 mg [dye free, no artificial color(s)]
Erythromycin lactobionate: Stable in NS; incompatible with D5LR, D10W.
Y-site administration: Incompatible with cefepime, fluconazole.
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification
Alfentanil: Macrolide Antibiotics may increase the serum concentration of Alfentanil. Management: For patients receiving an interacting macrolide antibiotic, caution should be used in administering alfentanil; monitor for increased anesthetic and respiratory depressant effects. Consider using lower doses of alfentanil or an alternative anesthetic. Consider therapy modification
ALPRAZolam: Macrolide Antibiotics may increase the serum concentration of ALPRAZolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification
Antineoplastic Agents (Vinca Alkaloids): Macrolide Antibiotics may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Macrolides may also increase the distribution of Vinca Alkaloids into certain cells and/or tissues. Management: Consider an alternative to using a macrolide antibiotic when possible in order to avoid the potential for increased vinca alkaloid toxicity. Consider therapy modification
Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy
Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination
ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy
Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination
AtorvaSTATin: Erythromycin (Systemic) may increase the serum concentration of AtorvaSTATin. Monitor therapy
Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification
Barnidipine: Erythromycin (Systemic) may increase the serum concentration of Barnidipine. Avoid combination
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy
Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy
Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination
Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination
Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy
Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy
Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification
Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination
Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification
BusPIRone: Macrolide Antibiotics may decrease the metabolism of BusPIRone. Consider therapy modification
Calcium Channel Blockers: Macrolide Antibiotics may decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Felodipine Canadian labeling specifically recommends avoiding its use in combination with clarithromycin. Exceptions: Clevidipine. Consider therapy modification
Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy
CarBAMazepine: Erythromycin (Systemic) may increase the serum concentration of CarBAMazepine. Management: Consider alternative antimicrobial therapy in combination with carbamazepine. If combined, monitor for increased carbamazepine effects/toxicities. Consider therapy modification
Cardiac Glycosides: Macrolide Antibiotics may increase the serum concentration of Cardiac Glycosides. Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination
Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification
Cisapride: Macrolide Antibiotics may decrease the metabolism of Cisapride. Avoid combination
Clindamycin (Topical): Erythromycin (Systemic) may diminish the therapeutic effect of Clindamycin (Topical). Avoid combination
Clopidogrel: Erythromycin (Systemic) may diminish the antiplatelet effect of Clopidogrel. Monitor therapy
CloZAPine: Erythromycin (Systemic) may enhance the adverse/toxic effect of CloZAPine. Monitor therapy
Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
CycloSPORINE (Systemic): Macrolide Antibiotics may decrease the metabolism of CycloSPORINE (Systemic). Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); Praziquantel; Vinorelbine. Monitor therapy
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Disopyramide: Macrolide Antibiotics may enhance the QTc-prolonging effect of Disopyramide. Macrolide Antibiotics may decrease the metabolism of Disopyramide. Avoid combination
Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination
Doxofylline: Erythromycin (Systemic) may increase the serum concentration of Doxofylline. Monitor therapy
DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification
Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification
Ergot Derivatives: Macrolide Antibiotics may increase the serum concentration of Ergot Derivatives. Cabergoline and Clarithromycin may interact, see specific monograph for full details. Exceptions: Cabergoline; Nicergoline. Consider therapy modification
Estazolam: Macrolide Antibiotics may increase the serum concentration of Estazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification
Etravirine: May decrease the serum concentration of Macrolide Antibiotics. Clarithromycin AUC is reduced and levels of the active metabolite (14-hydroxy-clarithromycin) are modestly increased. Management: For the treatment of Mycobacterium avium complex, consider changing to alternative agent, such as azithromycin. Consider therapy modification
Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification
FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification
Fexofenadine: Erythromycin (Systemic) may increase the serum concentration of Fexofenadine. Monitor therapy
Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination
Fluconazole: May enhance the QTc-prolonging effect of Erythromycin (Systemic). Fluconazole may increase the serum concentration of Erythromycin (Systemic). Avoid combination
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination
GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification
Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy
Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination
Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy
Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy
Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination
Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination
Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy
Lincosamide Antibiotics: May diminish the therapeutic effect of Erythromycin (Systemic). Avoid combination
Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination
Lovastatin: Erythromycin (Systemic) may increase the serum concentration of Lovastatin. Avoid combination
Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification
Mequitazine: Erythromycin (Systemic) may enhance the arrhythmogenic effect of Mequitazine. Management: Concurrent administration of intravenous erythromycin with mequitazine is contraindicated. Avoid combination
Midazolam: Macrolide Antibiotics may increase the serum concentration of Midazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification
MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination
Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination
Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy
Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination
OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy
PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy
Pimozide: Macrolide Antibiotics may enhance the QTc-prolonging effect of Pimozide. Macrolide Antibiotics may decrease the metabolism of Pimozide. This mechanism may not apply to azithromycin. Avoid combination
Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination
Pitavastatin: Erythromycin (Systemic) may increase the serum concentration of Pitavastatin. Management: Limit pitavastatin to a maximum of 1 mg/day (adult dose) when used in combination with erythromycin. If this combination is used, monitor patients more closely for evidence of pitavastatin toxicity. Consider therapy modification
Pravastatin: Erythromycin (Systemic) may increase the serum concentration of Pravastatin. Monitor therapy
QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy
QuiNIDine: Erythromycin (Systemic) may enhance the QTc-prolonging effect of QuiNIDine. Erythromycin (Systemic) may increase the serum concentration of QuiNIDine. Avoid combination
QuiNINE: Macrolide Antibiotics may increase the serum concentration of QuiNINE. Avoid combination
Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification
Repaglinide: Macrolide Antibiotics may increase the serum concentration of Repaglinide. Monitor therapy
Rifamycin Derivatives: Macrolide Antibiotics may decrease the metabolism of Rifamycin Derivatives. Exceptions: Rifapentine. Consider therapy modification
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy
Rilpivirine: Macrolide Antibiotics may increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Consider therapy modification
Rivaroxaban: Erythromycin (Systemic) may increase the serum concentration of Rivaroxaban. Management: In patients with impaired renal function, erythromycin should not be used unless the potential benefits outweigh the potential risks. This interaction is unlikely clinically significant in patients with normal renal function. Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy
SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy
Sertraline: Erythromycin (Systemic) may enhance the adverse/toxic effect of Sertraline. Monitor therapy
Sildenafil: Erythromycin (Systemic) may increase the serum concentration of Sildenafil. Management: For pulmonary arterial hypertension, US label recommends no dose adjustment and Canadian label recommends reducing to 20mg twice/day. For erectile dysfunction, consider using a lower starting dose of 25mg in patients who are also taking erythromycin. Consider therapy modification
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Simeprevir: May increase the serum concentration of Erythromycin (Systemic). Erythromycin (Systemic) may increase the serum concentration of Simeprevir. Avoid combination
Simvastatin: Erythromycin (Systemic) may increase the serum concentration of Simvastatin. Avoid combination
Sirolimus: Macrolide Antibiotics may decrease the metabolism of Sirolimus. Consider therapy modification
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification
Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification
St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification
Tacrolimus (Systemic): Erythromycin (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy
Tacrolimus (Topical): Macrolide Antibiotics may increase the serum concentration of Tacrolimus (Topical). Monitor therapy
Telaprevir: May increase the serum concentration of Erythromycin (Systemic). Erythromycin (Systemic) may increase the serum concentration of Telaprevir. Monitor therapy
Temsirolimus: Macrolide Antibiotics may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism. Consider therapy modification
Terfenadine: Macrolide Antibiotics may enhance the QTc-prolonging effect of Terfenadine. Macrolide Antibiotics may increase the serum concentration of Terfenadine. Avoid combination
Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy
Theophylline Derivatives: Macrolide Antibiotics may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Consider therapy modification
Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination
Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination
Triazolam: Macrolide Antibiotics may increase the serum concentration of Triazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification
Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy
Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination
Vardenafil: Erythromycin (Systemic) may increase the serum concentration of Vardenafil. Management: Limit dose of vardenafil film-coated tablets (Levitra) to 5 mg per 24 hours with concomitant use of erythromycin. Concomitant use of vardenafil orally disintegrating tablets (Staxyn) with erythromycin is not recommended. Consider therapy modification
Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification
Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination
Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination
Vitamin K Antagonists (eg, warfarin): Macrolide Antibiotics may increase the serum concentration of Vitamin K Antagonists. Monitor therapy
Zafirlukast: Erythromycin (Systemic) may decrease the serum concentration of Zafirlukast. Monitor therapy
Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification
False-positive urinary catecholamines (fluorometric assay), 17-hydroxycorticosteroids and 17-ketosteroids
Frequency not defined. Incidence may vary with formulation.
Cardiovascular: Local thrombophlebitis, prolonged Q-T interval on ECG, torsades de pointes, ventricular arrhythmia, ventricular tachycardia
Central nervous system: Seizure
Dermatologic: Erythema multiforme, pruritus, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria
Gastrointestinal: Abdominal pain, anorexia, diarrhea, nausea, oral candidiasis, pancreatitis, pseudomembranous colitis, pyloric stenosis (infantile hypertrophic), vomiting
Hepatic: Abnormal hepatic function tests, cholestatic jaundice (most common with estolate), hepatitis
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Local: Injection site phlebitis
Neuromuscular & skeletal: Weakness
Otic: Hearing loss
Renal: Interstitial nephritis
Postmarketing and/or case reports (Limited to important or life-threatening): Hepatotoxicity (idiosyncratic) (Chalasani, 2014)
Concerns related to adverse effects:
- Altered cardiac conduction: Macrolides have been associated with rare QTc prolongation and ventricular arrhythmias, including torsade de pointes; use with caution in patients at risk of prolonged cardiac repolarization; avoid use in patients with prolonged QT interval, uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, or concurrent use of Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents.
- Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns:
- Hepatic impairment: Use with caution in patients with preexisting liver disease; hepatic impairment, including hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been observed. Discontinue if symptoms of malaise, nausea, vomiting, abdominal colic, and fever.
- Myasthenia gravis: Exacerbation of and new onset of myasthenia gravis symptoms have been reported.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Major inhibitor of CYP3A4: Use caution with any agents with substantial metabolism through the CYP3A4 pathway; high potential for drug interactions exists. Avoid concurrent use with strong CYP3A4 inhibitors; may increase the risk of sudden cardiac death (Ray 2004).
Special populations:
- Infants: Use of erythromycin has been associated with infantile hypertrophic pyloric stenosis (IHPS); observe for non-bilious vomiting or irritability with feeding.
- Elderly: May be at increased risk of adverse events, including hearing loss and/or torsade de pointes, particularly if concurrent renal/hepatic impairment.
Dosage form specific issues:
- Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol ( ≥99 mg/kg/day) have been associated with a potentially fatal toxicity ( "gasping syndrome " �) in neonates; the "gasping syndrome " � consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP [Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer 's labeling.
B
Adverse events were not observed in animal reproduction studies. Erythromycin crosses the placenta and low concentrations are found in the fetal serum. Cardiovascular anomalies following exposure in early pregnancy have been reported in some observational studies. Serum concentrations of erythromycin may be variable in pregnant women (Kiefer 1955; Philipson 1976).
In patients with acute infections during pregnancy, erythromycin may be given if an antibiotic is required and appropriate based on bacterial sensitivity (ACOG No. 120 2011). Erythromycin is the antibiotic of choice for preterm premature rupture of membranes (with membrane rupture between 24 0/7 to 33 6/7 weeks gestation) (ACOG 2013), the treatment of lymphogranuloma venereum in pregnancy, and the treatment of or long-term suppression of Bartonella infection in HIV-infected pregnant patients. Erythromycin is one of the antibiotics that may be used for the treatment of chancroid or granuloma inguinale and during pregnancy, and may be appropriate as an alternative agent for the treatment of chlamydial infections in pregnant women (consult current guidelines) (CDC [Workowski 2015]; HHS [opportunistic; adult] 2015).
Inhibits RNA-dependent protein synthesis at the chain elongation step; binds to the 50S ribosomal subunit resulting in blockage of transpeptidation
Oral: Variable but better with salt forms than with base form; 18% to 45%; ethylsuccinate may be better absorbed with food (Thompson 1980).
Vd: 0.64 L/kg
Relative diffusion from blood into CSF: Minimal even with inflammation
CSF:blood level ratio: Normal meninges: 2% to 13%; Inflamed meninges: 7% to 25%
Demethylation primarily via hepatic CYP3A4
Primarily feces; urine (2% to 15% as unchanged drug)
Serum: Base: 4 hours; Ethylsuccinate: 0.5 to 2.5 hours; Stearate: 3 hours (Steigbigel 2000); delayed with food due to differences in absorption
Neonates ( ≤15 days of age): 2.1 hours; Adults: Peak: 1.5-2 hours; End-stage renal disease: 5-6 hours
Base: 73% to 81%
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience abdominal pain, nausea, vomiting, diarrhea, lack of appetite, or injection site irritation. Have patient report immediately to prescriber sings of myasthenia gravis, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), urinary retention, change in amount of urine passed, seizures, arrhythmia, or signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.