azithromycin (Rx)

>10%

High single dose therapy

• Diarrhea (52.8%)
• Nausea (32.6%)
• Abdominal pain (27%)
• Loose stool (19.1%)

1-10%

Elevated ALT, AST, creatinine (4-6%)

Elevated LDH, bilirubin (1-3%)

Community-acquired pneumonia

• Pain at injection site (6.5%)
• Diarrhea (4.3%)
• Nausea (3.9%)
• Local inflammation (3.1%)
• Abdominal pain (2.7%)
• Vomiting (1.4%)

Pelvic inflammatory disease

• Diarrhea (8.5%)
• Nausea (6.6%)
• Vaginitis (2.8%)
• Abdominal pain (1.9%)
• Anorexia (1.9%)
• Rash and pruritus (1.9%)

<1%

Dyspepsia

Flatulence

Mucositis

Oral Moniliasis

Gastritis

Headache

Somnolence

Bronchospasm

Taste perversion

Leukopenia

Neutropenia

Decreased platelet count

Elevated serum alkaline phosphatase

Postmarketing Reports

Allergic: Arthralgia, edema, urticaria and angioedema

Cardiovascular: Arrhythmias (eg, ventricular tachycardia), hypotension, QT prolongation, and torsades de pointes

Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and reports of tongue discoloration

General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (including fatalities).

Genitourinary: Interstitial nephritis and acute renal failure and vaginitis

Hematopoietic: Thrombocytopenia

Liver/biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure

Nervous system: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope

Psychiatric: Aggressive reaction and anxiety

Skin/appendages: Pruritus, serious skin reactions including, erythema multiforme, AGEP, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS

Special senses: Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss

Contraindications

Hypersensitivity to azithromycin, erythromycin, any macrolides or ketolides

History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin

Cautions

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death; discontinue treatment immediately if signs and symptoms of hepatitis occur

Infantile Hypertrophic Pyloric Stenosis (IHPS) has been reported; advise direct parents and caregivers if vomiting or irritability with feeding occurs

Clostridium difficile associated diarrhea (CDAD) has been reported, and may range in severity from mild diarrhea to fatal colitis; if CDAD is suspected or confirmed, discontinue ongoing antibacterial use not directed against C. difficile; institute appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation as clinically indicated

Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported

Antibacterial agents used to treat nongonococcal urethritis may mask or delay the symptoms of incubating syphilis; all patients with sexually transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate testing for gonorrhea performed at the time of diagnosis; if infection confirmed, initiate appropriate antibacterial therapy and follow-up tests for these diseases

Local IV site reactions have been reported with IV azithromycin

Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria

QT prolongation

• Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been reported with macrolides, including azithromycin
• Elderly patients may be more susceptible to drug-associated effects on the QT interval

• Consider the risk of QT prolongation for at-risk groups including:

  • Patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure
  • Patients on drugs known to prolong the QT interval
  • Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents

Hypersensitivity

• Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported
• Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported
• If an allergic reaction occurs, discontinue drug and institute appropriate therapy
• Be aware that allergic symptoms may reappear after symptomatic therapy has been discontinued

Drug interaction overview

• Coadministration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations; closely monitor for adverse reactions of azithromycin
• Spontaneous postmarketing reports suggest that coadministration of azithromycin may potentiate the effects of oral anticoagulants (eg, warfarin), although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin; carefully monitor prothrombin time while patients are receiving azithromycin and oral anticoagulants concomitantly
• Drug interactions with digoxin, colchicine or phenytoin have been observed when combined other macrolide; until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised

Bronchiolitis obliterans

• August 3, 2018: FDA issues warning letter to healthcare providers
• Increased relapse and mortality observed with azithromycin in the clinical trial entitled ALLOZITHRO (evaluation of the efficacy of azithromycin to prevent bronchiolitis obliterans syndrome [BOS] after allogenic hematopoietic stem cell transplantation [HSCT])
• The study was terminated early after an increased risk of relapses was observed in patients taking azithromycin compared with placebo
• Azithromycin is not indicated for prophylaxis of bronchiolitis obliterans syndrome (BOS) in patients undergoing HSCT and should not be used off-label for this condition

Pregnancy

Available data on use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes

Animal data

• Decreased viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day 6 of pregnancy through weaning at a dose equivalent to 4 times an adult human daily dose of 500 mg based on body surface area

Lactation

Present in human milk

Non-serious adverse reactions have been reported in breastfed infants after maternal administration of azithromycin

No data available on the effects of azithromycin on milk production

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for azithromycin and any potential adverse effects on the breastfed infant from azithromycin or from the underlying maternal condition

Clinical considerations

Advise women to monitor the breastfed infant for diarrhea, vomiting, or rash

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Binds to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest; does not affect nucleic acid synthesis

Concentrates in phagocytes and fibroblasts, as demonstrated by in vitro incubation techniques; in vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues

Absorption

Absolute bioavailability: 38% (250-mg capsules)

Peak plasma concentration

• Oral (3-day regimen): 0.44 mcg/mL (Day 1); 0.54 mcg/mL (Day 3)
• Oral (5-day regimen): 0.43 mcg/mL (Day 1); 0.24 mcg/mL (Day 5)
• IV: 1.14 mcg/mL (healthy volunteers); 3.63 mcg/mL (hospitalized patients)

AUC

• Oral (3-day regimen): 17.4 mcg⋅hr/mL
• Oral (5-day regimen): 154.9 mcg⋅hr/mL
• IV: 8.03 mcg⋅hr/mL (healthy volunteers); 9.6 mcg⋅hr/mL (hospitalized patients)

Effects of food

• Oral suspension: When administered with food, peak plasma concentration increased by 56% and AUC unchanged
• Tablets: No effect

Distribution

Protein bound: 51% (0.02 mcg/mL); 7% (2 mcg/mL)

Elimination

Clearance: 630 mL/min (single 500-mg oral and IV dose)

Half-life

• Oral (3-day regimen): 71.8 hr
• Oral (5-day regimen): 68.9 hr

Excretion

• IV, 1st dose: 11%
• IV, 5th dose: 14%
• Oral: 6% (unchanged)
• Biliary excretion is a major route of elimination for unchanged drug, following oral administration

IV Incompatibilities

Y-site: Amikacin, aztreonam, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, clindamycin, droperidol, famotidine, fentanyl, furosemide, gentamicin, imipenem, cilastatin, ketorolac, levofloxacin, morphine, piperacillin-tazobactam, ondansetron(?), potassium chloride, ticarcillin-clavulanate, tobramycin

Other IV substances, additives, or medications should not be added to azithromycin, or infused simultaneously through the same IV line

IV Compatibilities

0.9% NaCl

0.45% NaCl)

Dextrose 5% in Water (D5W)

Lactated Ringer Solution (LR)

D5W in 0.45% NaCl with 20 mEq KCl

D5W in LR

D5W in 0.3% NaCl

D5W in 0.45% NaCl

Normosol-M in D5W

Normosol-R in D5W

IV Preparation

Add 4.8 mL of sterile water for injection to 500-mg vial; final concentration is (100 mg/mL); shake vial until all of the drug is dissolved

Visually inspect vial for particulate matter before administration; discard if particular matter is present

Dilute reconstituted drug in either a 250-mL (final concentration 2 mg/mL) or 500-mL IV bag (final concentration 1 mg/mL)

IV Administration

1 mg/mL diluted solution: Infuse over 3 hr

2mg/mL diluted solution: Infuse over 1 hr

Oral Suspension Preparation

Final concentration after reconstitution is 100 mg/5 mL

• Add 9 mL of water to 300-mg bottle

Final concentration after reconstitution is 200 mg/5 mL

• Add 9 mL of water to 600-mg bottle
• Add 12 mL of water to 900-mg bottle
• Add 15 mL of water to 1200-mg bottle

Oral Administration

Tablets and oral suspension: Take with or without food

Oral suspension: Shake well before use; refer to prescribing information for dosing information

Storage

Unopened vial: Store at <30ºC (86ºF)

Reconstituted vial: Store at <30ºC (86ºF) for 24 hr

Diluted solutions: Store <30ºC (86ºF) for 24 hr OR refrigerate at 5ºC (41ºF)

Reconstituted oral suspension: Store at 5-30ºC (41-86ºF) and use within 10 days; discard after full dosing is completed