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Azithromycin (Systemic)

Pronunciation

Pronunciation

(az ith roe MYE sin)

Index Terms

  • Azithromycin Dihydrate
  • Azithromycin Monohydrate
  • Z-Pak
  • Zithromax TRI-PAK
  • Zithromax Z-PAK

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Packet, Oral:

Zithromax: 1 g (3 ea, 10 ea) [cherry-banana flavor]

Generic: 1 g (3 ea, 10 ea)

Solution Reconstituted, Intravenous:

Zithromax: 500 mg (1 ea)

Generic: 500 mg (1 ea); 2.5 g (1 ea [DSC])

Solution Reconstituted, Intravenous [preservative free]:

Generic: 500 mg (1 ea)

Suspension Reconstituted, Oral:

Zithromax: 100 mg/5 mL (15 mL) [cherry-vanilla-banana flavor]

Zithromax: 200 mg/5 mL (15 mL, 22.5 mL, 30 mL) [cherry flavor]

Zmax: 2 g (1 ea) [cherry-banana flavor]

Generic: 100 mg/5 mL (15 mL); 200 mg/5 mL (15 mL, 22.5 mL, 30 mL)

Tablet, Oral:

Zithromax: 250 mg, 500 mg, 600 mg

Zithromax Tri-Pak: 500 mg

Zithromax Z-Pak: 250 mg

Generic: 250 mg, 500 mg, 600 mg

Brand Names: U.S.

  • Zithromax
  • Zithromax Tri-Pak
  • Zithromax Z-Pak
  • Zmax

Pharmacologic Category

  • Antibiotic, Macrolide

Pharmacology

Inhibits RNA-dependent protein synthesis at the chain elongation step; binds to the 50S ribosomal subunit resulting in blockage of transpeptidation

Absorption

Oral: Rapid from the GI tract

Distribution

Extensive tissue; distributes well into skin, lungs, sputum, tonsils, and cervix; penetration into CSF is poor; Vd: 31-33 L/kg

Metabolism

Hepatic to inactive metabolites

Excretion

Oral, IV: Biliary (major route 50%, unchanged); urine (6% to 14% unchanged)

Time to Peak

Oral: Serum: Immediate release: ~2 to 3 hours; Extended release: 3 to 5 hours

Half-Life Elimination

Terminal: Oral, IV: Infants and Children 4 months to 15 years: 54.5 hours; Adults: Immediate release: 68-72 hours; Extended release: 59 hours

Protein Binding

Concentration dependent and dependent on alpha1-acid glycoprotein concentrations: Oral, IV: 7% to 51%

Special Populations: Renal Function Impairment

Cmax and AUC increased 61% and 35%, respectively, in subjects with severe renal impairment.

Special Populations: Elderly

In elderly women, a higher Cmax was observed but there was no change in drug accumulation.

Use: Labeled Indications

Oral, IV: Treatment of acute otitis media due to H. influenzae, M. catarrhalis, or S. pneumoniae; pharyngitis/tonsillitis due to S. pyogenes, community-acquired pneumonia due to Chlamydia (also known as Chlamydophila) pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae; pelvic inflammatory disease (PID) due to C. trachomatis, N. gonorrhoeae, or M. hominis; genital ulcer disease (in men) due to H. ducreyi (chancroid); acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) due to H. influenzae, M. catarrhalis, or S. pneumoniae; acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae; prevention of Mycobacterium avium complex (MAC) (alone or in combination with rifabutin) in patients with advanced HIV infection; treatment of disseminated MAC (in combination with ethambutol) in patients with advanced HIV infection; skin and skin structure infections (uncomplicated) due to S. aureus, S. pyogenes, or S. agalactiae; urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae

Limitations of use (tablets, oral suspension, Zmax only): Not recommended for use in patients with moderate to severe pneumonia with any of the following concomitant conditions: cystic fibrosis, nosocomial infections, known or suspected bacteremia, hospitalized, elderly or debilitated or significant health problems that affect the ability to respond to illness (eg, immunodeficiency, functional asplenia).

Use: Unlabeled

Treatment of babesiosis; cat scratch disease; gonococcal infections of the pharynx or rectum (combination therapy) and expedited partner therapy; granuloma inguinale (donovanosis); Mycoplasma genitalium infections; pertussis; prophylaxis of infective endocarditis in select patients who are allergic to penicillin and undergoing dental procedures; prevention of pulmonary exacerbations in patients with noncystic fibrosis bronchiectasis; treatment of Shigella dysenteriae type 1

Contraindications

Hypersensitivity to azithromycin, erythromycin, other macrolide (eg, azalide or ketolide) antibiotics, or any component of the formulation; history of cholestatic jaundice/hepatic dysfunction associated with prior azithromycin use

Note: The manufacturer does not list concurrent use of pimozide as a contraindication; however, azithromycin is listed as a contraindication in the manufacturer’s labeling for pimozide.

Dosing: Adult

Note: Extended release suspension (Zmax) is not interchangeable with immediate release formulations. Use should be limited to approved indications. All doses are expressed as immediate release azithromycin unless otherwise specified.

Acne vulgaris (off-label use): Oral: Dosing regimens used in clinical trials have varied greatly. All trials used pulse-dosing regimens; regimens included: 500 mg once daily for 4 consecutive days per month for 3 consecutive months (Babaeinejad 2011; Parsad 2001) or 500 mg once daily for 3 days in the first week, followed by 500 mg once weekly until week 10 (Maleszka 2011) or 500 mg once daily for 3 consecutive days each week in month 1, followed by 500 mg once daily for 2 consecutive days each week in month 2, then 500 mg once daily for 1 day each week in month 3 (Kus 2005). The shortest possible duration should be used to minimize development of bacterial resistance; re-evaluate at 3 to 4 months (AAD [Zaenglein 2016]).

Babesiosis (off-label use): Oral: 500 to 1,000 mg on day 1, followed by 250 mg once daily for 7 to 10 days with atovaquone; higher doses may be required in immunocompromised patients (600 to 1,000 mg daily). Note: Relapsing infection may require at least 6 weeks of therapy (Krause 2000; Vannier 2012; IDSA [Wormser 2006]).

Bacterial sinusitis: Oral: 500 mg daily for a total of 3 days

Extended release suspension (Zmax): 2 g as a single dose

Bronchiolitis obliterans syndrome (off-label use): Oral: 250 mg daily for 5 days, followed by 250 mg 3 times per week for a minimum of 3 months (Meyer 2014). Note: It is unclear whether azithromycin should be continued long-term if a benefit is observed or if it should be discontinued if lung function does not improve (Meyer 2014).

Cat scratch disease (off-label use): Oral: ≥45.5 kg: 500 mg as a single dose, then 250 mg once daily for 4 additional days (Bass 1998; Stevens 2014)

Chancroid due to H. ducreyi: Oral: 1 g as a single dose. Note: Data are limited concerning the efficacy in HIV infected patients (CDC [Workowski 2015]).

Chlamydia trachomatis infection: Oral: 1 g as a single dose (CDC [Workowski 2015])

Community-acquired pneumonia:

Oral: 500 mg on day 1 followed by 250 mg once daily on days 2 to 5

Extended release suspension (Zmax): 2 g as a single dose

IV: 500 mg as a single dose for at least 2 days, follow IV therapy by the oral route with a single daily dose of 500 mg to complete a 7- to 10-day course of therapy.

Disseminated M. avium complex disease in patients with advanced HIV infection: Oral:

Treatment: 600 mg daily in combination with ethambutol

Primary prophylaxis: 1,200 mg once weekly (preferred), with or without rifabutin or alternatively, 600 mg twice weekly (DHHS 2013)

Secondary prophylaxis: 500 to 600 mg daily in combination with ethambutol (DHHS 2013)

Gonococcal infection, conjunctivitis (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (CDC [Workowski 2015])

Gonococcal infection, disseminated (arthritis, arthritis-dermatitis, meningitis, endocarditis) (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (CDC [Workowski 2015])

Gonococcal infection, expedited partner therapy (off-label use): Oral: 1 g as a single dose in combination with cefixime (CDC [Workowski 2015]). Note: To be used only for heterosexual partners with gonorrhea if health department partner-management strategies are impractical/unavailable and there is concern by the provider for the prompt evaluation and treatment of the partner; medication may be delivered to partner by patient, collaborating pharmacy, or disease investigation specialist as permitted by law; written materials to educate partners about their exposure to gonorrhea, importance of therapy, and when to seek clinical evaluation for adverse reactions/complications must also be provided with the medication (CDC [Workowski 2015]).

Gonococcal infection, uncomplicated (cervix, rectum [off-label use], urethra) (off-label regimen): Oral: 1 g as a single dose in combination with ceftriaxone (preferred) or cefixime (only if ceftriaxone unavailable) (CDC [Workowski 2015]).

Patients with severe cephalosporin allergy (off-label regimen): 2 g as a single dose in combination with gemifloxacin or gentamicin IM (CDC [Workowski 2015])

Gonococcal infection, uncomplicated (pharynx) (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (CDC [Workowski 2015])

Granuloma inguinale (donovanosis) (off-label use): Oral: 1 g once weekly or 500 mg once daily for at least 3 weeks and until lesions have healed. Note: If symptoms do not improve within the first few days of therapy, the addition of gentamicin may be considered (CDC [Workowski 2015])

Helicobacter pylori infection (off-label use): Oral: 500 mg once daily for 3 to 7 days in combination with an acid-reducing drug and other antibiotics (Laine 1999; Trevisani 1998)

Infection prophylaxis in neutropenia (off-label use): Oral: 250 mg once daily; initiate at the time of stem cell infusion and continue until recovery from neutropenia or initiation of empiric antibiotics for neutropenic fever (IDSA [Freifeld 2011]; Tomblyn 2009).

Mild to moderate respiratory tract, skin, and soft tissue infections: Oral: 500 mg in a single loading dose on day 1 followed by 250 mg daily as a single dose on days 2 to 5

Alternative regimen: Bacterial exacerbation of COPD: 500 mg daily for a total of 3 days

Mycoplasma genitalium (off-label use) (Falk 2015; CDC [Workowski 2015]): Oral:

Single-dose regimen: 1 g as a single dose

Extended-dose regimen: 500 mg on day 1, followed by 250 mg once daily on days 2 through 5

Pelvic inflammatory disease (PID): IV: 500 mg as a single dose for 1 to 2 days, follow IV therapy by the oral route with a single daily dose of 250 mg to complete a 7-day course of therapy.

Pertussis (off-label use) (CDC 2005): Oral: 500 mg on day 1 followed by 250 mg daily on days 2 to 5 (maximum: 500 mg daily)

Pharyngitis (including susceptible group A streptococci), tonsillitis (as an alternative agent in penicillin-allergic patients): Oral: 12 mg/kg (maximum: 500 mg) on day 1 followed by 6 mg/kg (maximum: 250 mg) once daily on days 2 through 5. Note: Regimen is also recommended by the Infectious Disease Society of America (IDSA) (Shulman 2012).

Prevention of pulmonary exacerbations in patients with noncystic fibrosis bronchiectasis (off-label use): Oral: 500 mg 3 days per week. Note: Duration of treatment in clinical trial was 6 months; durations >6 months have not been evaluated. Trial patients had ≥1 exacerbation in the past year, no macrolide treatment for >3 months in the past 6 months, and were screened for nontuberculous mycobacterial infection prior to treatment (Wong 2012). A more selective approach for patients with functionally mild disease has been suggested (Wilson 2012).

Prophylaxis against infective endocarditis (off-label use): Oral: 500 mg 30 to 60 minutes prior to the procedure. Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA.

Prophylaxis against sexually transmitted diseases following sexual assault (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (plus metronidazole or tinidazole) (CDC [Workowski 2015])

Shigella dysentery type 1 (off-label use): Oral: 1,000 to 1,500 mg once daily for 1 to 5 days (WHO 2005)

Traveler’s diarrhea (off-label use): Oral: 1,000 mg as a single dose or 500 mg once daily for 1 to 3 days with or without concomitant loperamide (CDC 2015; Ericsson 2007; Tribble 2007). Note: Increased nausea may occur with the 1,000 mg single dose regimen (Tribble 2007).

Urethritis/cervicitis (nongonococcal): Oral: 1 g as a single dose

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Extended release suspension (Zmax) is not interchangeable with immediate release formulations. Use should be limited to approved indications. All doses are expressed as immediate release azithromycin unless otherwise specified.

Note: Adolescents ≥16 years: Refer to adult dosing.

Acne vulgaris (off-label use): Adolescents ≥13 years: Oral: Dosing regimens used in clinical trials have varied greatly. All trials used pulse-dosing regimens; regimens include: 500 mg once daily for 4 consecutive days per month for 3 consecutive months (Babaeinejad 2011) or 500 mg once daily for 3 days in the first week, followed by 500 mg once weekly until week 10 (Maleszka 2011). The shortest possible duration should be used to minimize development of bacterial resistance; re-evaluate at 3 to 4 months (AAD [Zaenglein 2016])

Bacterial sinusitis: Children ≥6 months: Oral: 10 mg/kg once daily for 3 days (maximum: 500 mg daily)

Cat scratch disease (off-label use) (Bass 1998; Stevens 2014): Oral:

<45.5 kg: 10 mg/kg as a single dose, then 5 mg/kg once daily for 4 additional days

≥45.5 kg: Refer to adult dosing.

Chlamydia trachomatis infection (off-label use): Oral: Children ≥45 kg: 1 g as a single dose (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 mild infection or step-down therapy, atypical (M. pneumoniae, Chlamydophila [also known as Chlamydia] pneumoniae, C. trachomatis) (preferred): Oral: 10 mg/kg (maximum dose: 500 mg) as a single dose on the first day, followed by 5 mg/kg/day (maximum dose: 250 mg) on days 2 through 5.

Presumed moderate to severe infection, atypical (M. pneumoniae, Chlamydophila [also known as Chlamydia] pneumoniae, C. trachomatis) : IV: 10 mg/kg/day on days 1 and 2, then switch to oral azithromycin therapy if possible to finish the 5-day course

Alternative regimens for community-acquired pneumonia: Oral: 10 mg/kg (maximum dose: 500 mg) once daily for 3 days (Kogan 2003)

Extended release suspension (Zmax): Infants ≥6 months and Children: Oral

<75 lbs (34 kg): 60 mg/kg as a single dose

≥75 lbs (34 kg): Refer to adult dosing

Disseminated M. avium complex disease in patients with advanced HIV infection (off-label use) (DHHS 2013): Oral:

Treatment: 10 to 12 mg/kg/day (maximum: 500 mg) in combination with ethambutol; patients with severe disease should also receive rifabutin

Primary prophylaxis: 20 mg/kg (maximum: 1,200 mg) once weekly (preferred) or alternatively, 5 mg/kg/day once daily (maximum: 250 mg daily)

Secondary prophylaxis: 5 mg/kg/day once daily (maximum: 250 mg daily) in combination with ethambutol, with or without rifabutin

Gonococcal infection, conjunctivitis (off-label use): Adolescents: Refer to adult dosing.

Gonococcal infection, disseminated (arthritis, arthritis-dermatitis, meningitis, endocarditis) (off-label use): Adolescents: Refer to adult dosing.

Gonococcal infection, uncomplicated (cervix, rectum [off-label use], urethra) (off-label regimen): Adolescents: Refer to adult dosing.

Gonococcal infection, uncomplicated (pharynx) (off-label use): Adolescents: Refer to adult dosing.

Otitis media: Children ≥6 months: Oral:

1-day regimen: 30 mg/kg as a single dose (maximum dose: 1,500 mg)

3-day regimen: 10 mg/kg once daily for 3 days (maximum: 500 mg daily)

5-day regimen: 10 mg/kg on day 1 (maximum: 500 mg daily) followed by 5 mg/kg/day once daily on days 2 to 5 (maximum: 250 mg daily)

Pertussis (off-label use) (CDC 2005): Oral:

Children <6 months: 10 mg/kg/day for 5 days

Children ≥6 months: 10 mg/kg on day 1 (maximum: 500 mg daily) followed by 5 mg/kg/day once daily on days 2 to 5 (maximum: 250 mg daily)

Pharyngitis (including susceptible group A streptococci), tonsillitis (as an alternative agent in penicillin allergic patients):

Manufacturer’s labeling and AHA/AAP recommendations: Children ≥2 years and Adolescents: Oral: 12 mg/kg/dose once daily for 5 days (maximum: 500 mg daily) (AHA guidelines [Gerber 2009]; Red Book [AAP 2012])

Alternative recommendations:

Children and Adolescents (off-label dose/regimen): Oral: Suspension: 20 mg/kg once daily for 3 days (maximum dose/day: 1,000 mg) (Cohen 2004; O’Doherty 1996)

Children and Adolescents: Oral: 12 mg/kg (maximum: 500 mg) on day 1 followed by 6 mg/kg/dose (maximum: 250 mg) once daily on days 2 through 5 (IDSA guidelines [Shulman 2012])

Prophylaxis against infective endocarditis (off-label use): Oral: 15 mg/kg 30 to 60 minutes before procedure. Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA.

Prophylaxis against sexually transmitted diseases following sexual assault (off-label use): Adolescents: Refer to adult dosing.

Shigella dysentery type 1 (off-label use): Oral: 6 to 20 mg/kg/day for 1 to 5 days (WHO 2005)

Dosing: Renal Impairment

Use with caution in patients with GFR <10 mL/minute (AUC increased by 35% compared to patients with normal renal function); however, no dosage adjustment is provided in the manufacturer’s labeling.

No supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis, peritoneal dialysis, or continuous renal replacement therapy (eg, CVVHD) (Aronoff 2007; Heintz 2009).

Dosing: Hepatic Impairment

Azithromycin is predominantly hepatically eliminated; however, there is no dosage adjustment provided in the manufacturer’s labeling, Use with caution due to potential for hepatotoxicity (rare); discontinue immediately for signs or symptoms of hepatitis.

Reconstitution

Injection (Zithromax): Prepare initiation solution by adding 4.8 mL of sterile water for injection to the 500 mg vial (resulting concentration: 100 mg/mL). Use of a standard syringe is recommended due to the vacuum in the vial (which may draw additional solution through an automated syringe).

The initial solution should be further diluted to a concentration of 1 mg/mL (500 mL) to 2 mg/mL (250 mL) in NS, D5W, or LR.

Administration

IV: Infuse over 1 hour (2 mg/ml infusion) or over 3 hours (1 mg/ml infusion). Not for IM or IV bolus administration.

Oral: Immediate release suspension and tablet may be taken without regard to food; extended release suspension should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal), within 12 hours of reconstitution.

Dietary Considerations

Some products may contain sodium and/or sucrose.

Oral suspension, immediate release, may be administered with or without food.

Oral suspension, extended release, should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal).

Tablet may be administered with food to decrease GI effects.

Compatibility

Stable in D5W, D5LR, D51/4NS, D51/3NS, D51/2NS (with or without 20 mEq/L KCl), Normosol®-M in D5, Normosol®-R in D5, LR, NS, 1/2NS.

Y-site administration: Incompatible with amikacin, aztreonam, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, clindamycin, famotidine, fentanyl, furosemide, gentamicin, imipenem/cilastatin, ketorolac, levofloxacin, morphine, piperacillin/tazobactam, potassium chloride, ticarcillin/clavulanate potassium, tobramycin.

Compatibility in syringe: Incompatible with ceftriaxone.

Storage

Injection (Zithromax): Store intact vials of injection at room temperature. Reconstituted solution is stable for 24 hours when stored below 30°C (86°F). The diluted solution D5W, D5LR, D51/4NS, D51/3NS, D51/2NS (with or without 20 mEq/L KCl), Normosol-M in D5, Normosol-R in D5, LR, NS, or 1/2NS is stable for 24 hours at or below room temperature (30°C [86°F]) and for 7 days if stored under refrigeration (5°C [41°F]).

Suspension, immediate release (Zithromax): Store dry powder below 30°C (86°F). Store reconstituted suspension at 5°C to 30°C (41°F to 86°F) and use within 10 days.

Suspension, extended release (Zmax): Store dry powder ≤30°C (86°F). Following reconstitution, store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not refrigerate or freeze. Should be consumed within 12 hours following reconstitution.

Tablet (Zithromax): Store between 15°C to 30°C (59°F to 86°F).

Drug Interactions

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

Amiodarone: Azithromycin (Systemic) may enhance the QTc-prolonging effect of Amiodarone. Management: The concomitant use of amiodarone, which has a high risk for QTc prolongation, with azithromycin, which may also prolong the QT interval, should be avoided. Avoid combination

AtorvaSTATin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of AtorvaSTATin. Monitor therapy

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

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

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

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

CycloSPORINE (Systemic): Macrolide Antibiotics may decrease the metabolism of CycloSPORINE (Systemic). 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

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

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

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

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Ivermectin (Systemic): Azithromycin (Systemic) may increase the serum concentration of Ivermectin (Systemic). Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Lovastatin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of Lovastatin. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nelfinavir: May increase the serum concentration of Azithromycin (Systemic). Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

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

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

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

QuiNINE: Macrolide Antibiotics may increase the serum concentration of QuiNINE. Avoid combination

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

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

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Simvastatin: Azithromycin (Systemic) may enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Monitor therapy

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

Tacrolimus (Systemic): Azithromycin (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

Terfenadine: Macrolide Antibiotics may enhance the QTc-prolonging effect of Terfenadine. Macrolide Antibiotics may increase the serum concentration of Terfenadine. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

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

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

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

Adverse Reactions

>10%: Gastrointestinal: Loose stools (≤14%; single-dose regimens tend to be associated with increased incidence), vomiting (children, single-dose regimens tend to be associated with increased incidence: 1% to 14%; adults: ≤2%; adults, single 2 g dose: 1% to 7%), diarrhea (2% to 9%; single-dose regimens 4% to 14%), nausea (≤7%; high single-dose regimens 4% to 18%)

1% to 10%:

Cardiovascular: Chest pain (≤1%), palpitations (≤1%)

Central nervous system: Dizziness (≤1%), drowsiness (≤1%), fatigue (≤1%), headache (≤1%), vertigo (≤1%)

Dermatologic: Skin rash (≤5%; single-dose regimens tend to be associated with increased incidence), dermatitis (children: ≤2%), pruritus (≤2%), skin photosensitivity (≤1%)

Endocrine & metabolic: Increased lactate dehydrogenase (1% to 3%), increased gamma-glutamyl transferase (1% to 2%), increased serum potassium (1% to 2%), decreased serum bicarbonate (adults: ≥1%), decreased serum glucose (adults: >1%)

Gastrointestinal: Abdominal pain (1% to 7%; single-dose regimens tend to be associated with increased incidence), anorexia (≤2%), dysgeusia (≤1%), dyspepsia (≤1%), flatulence (≤1%), gastritis (≤1%), melena (adults, multiple-dose regimens: ≤1%), mucositis (≤1%), oral candidiasis (≤1%)

Genitourinary: Vaginitis (≤3%), genital candidiasis (adults, multiple-dose regimens: ≤1%)

Hematologic & oncologic: Decrease in absolute neutrophil count (children: 15% to 16%; 500 to 1500 cells/mm3), decreased hematocrit (adults: >1%), decreased hemoglobin (adults: >1%), increased neutrophils (adults: >1%), thrombocythemia (adults: >1%), change in neutrophil count (children: ≥1%), eosinophilia (≥1%), lymphocytopenia (≥1%)

Hepatic: Increased serum ALT (≤6%), increased serum AST (≤6%), increased serum bilirubin (≤3%), cholestatic jaundice (≤1%)

Local (adults with IV administration): Pain at injection site (7%), local inflammation (3%)

Neuromuscular & skeletal: Increased creatine phosphokinase (1% to 2%)

Renal: Increased serum creatinine (≤6%), increased blood urea nitrogen (≤1%), nephritis (adults, multiple-dose regimens: ≤1%)

Respiratory: Bronchospasm (≤1%)

Miscellaneous: Fever (children: (≤2%)

<1% (Limited to important or life-threatening): Abnormal stools, acute renal failure, ageusia, aggressive behavior, agitation, alteration in sodium, altered sense of smell, altered serum glucose, anaphylaxis, anemia, angioedema, anosmia, anxiety, arthralgia, asthma, basophilia, bronchitis, cardiac arrhythmia, change in serum potassium, Clostridium difficile associated diarrhea, conjunctivitis (children), constipation, convulsions, cough, deafness, decreased serum potassium, decreased serum sodium, diaphoresis, DRESS syndrome, dyspnea, dysuria, eczema, edema, emotional lability, enteritis, erythema multiforme, exacerbation of myasthenia gravis, facial edema, flu-like symptoms (children), fungal dermatitis (children), fungal infection (children), gastrointestinal disease, hearing loss, hepatic failure, hepatic insufficiency, hepatic necrosis, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2014), hostility, hyperactivity, hyperkinesia, hypersensitivity reaction, hypotension, increased monocytes, increased serum alkaline phosphatase, increased serum bicarbonate, increased serum phosphate, interstitial nephritis, insomnia, irritability, jaundice, Lambert-Eaton syndrome, leukopenia, maculopapular rash, malaise, nervousness, neutropenia, otitis media, pain, pancreatitis, paresthesia, pharyngitis, pleural effusion, prolonged Q-T interval on ECG, pseudomembranous colitis, pyloric stenosis, pyloric stenosis (infantile hypertrophic), rhinitis, seizure, Stevens-Johnson syndrome, syncope, thrombocytopenia, tinnitus, tongue discoloration, toxic epidermal necrolysis, urticaria, ventricular tachycardia, vesiculobullous dermatitis, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Allergic reactions (eg, angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported (rare), including fatalities; reappearance of allergic reaction may occur shortly after discontinuation of symptomatic treatment without further azithromycin exposure.

• Altered cardiac conduction: Macrolides (especially erythromycin) have been associated with rare QTc prolongation and ventricular arrhythmias, including torsade de pointes; consider avoiding use in patients with prolonged QT interval, congenital long QT syndrome, history of torsade de pointes, bradyarrhythmias, uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, uncompensated heart failure, or concurrent use of Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval.

• Cardiac risk: A retrospective cohort study done in Tennessee Medicaid patients demonstrated an increased cardiac risk with azithromycin relative to amoxicillin or ciprofloxacin, and similar risk compared to levofloxacin; notably, increased cardiac mortality (an estimated 47 additional deaths per 1 million 5-day courses of treatment compared to amoxicillin) was associated with higher baseline cardiovascular risk (Ray 2012); however, these data may not be generalizable to the population as a whole (Ray 1989). In another retrospective population study of U.S. veterans, azithromycin was shown to significantly increase the risk of mortality and arrhythmia on days 1 to 5, but not on days 6 to 10 after dispensing the prescription (Rao 2014). In contrast, 2 additional large retrospective cohort studies did not demonstrate an increased risk of cardiovascular events, including all-cause mortality or cardiovascular death (Svanstrom 2013; Mortensen 2014). The implications of these data have yet to be determined.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD); CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Gonorrhea/syphilis: May mask or delay symptoms of incubating gonorrhea or syphilis, so appropriate culture and susceptibility tests should be performed prior to initiating a treatment regimen.

• Hepatic impairment: Use with caution in patients with preexisting liver disease; hepatocellular and/or cholestatic hepatitis, with or without jaundice, hepatic necrosis, failure, and death have occurred. Discontinue immediately if symptoms of hepatitis occur (malaise, nausea, vomiting, abdominal colic, fever).

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation and new onset of symptoms have occurred.

• Renal impairment: Use with caution in patients with severe renal impairment (GFR <10 mL/minute); increased gastrointestinal adverse effects may occur.

Special populations:

• Infants: Use of azithromycin in neonates and infants (treatment up to 42 days of life) has been associated with infantile hypertrophic pyloric stenosis (IHPS); observe for non-bilious vomiting or irritability with feeding (Eberly 2015).

Dosage form specific issues:

• Oral suspensions: Immediate release and extended release suspensions are not interchangeable.

Monitoring Parameters

Liver function tests, CBC with differential

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Azithromycin crosses the placenta (Ramsey 2003). The maternal serum half-life of azithromycin is unchanged in early pregnancy and decreased at term; however, high concentrations of azithromycin are sustained in the myometrium and adipose tissue (Fischer 2012; Ramsey 2003). Azithromycin is recommended for the treatment of several infections, including chlamydia, gonococcal infections, and Mycobacterium avium complex (MAC) in pregnant patients (consult current guidelines) (CDC [Workowski 2015]; HHS [opportunistic; adult] 2015).

Patient Education

• 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, diarrhea, headache, nausea, vomiting, itching, or lack of appetite. Have patient report immediately to prescriber tachycardia, abnormal heartbeat, hearing impairment, angina, muscle pain, joint pain, tinnitus, seizures, severe dizziness, passing out, difficulty swallowing, difficulty speaking, enlarged lymph nodes, vaginitis, signs of Clostridium difficile (C. diff)-associated diarrhea (abdominal pain or cramps, severe diarrhea or watery stools, or bloody stools), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), 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), or injection site irritation (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 health care 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.

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